Over the course of several decades,robust research has firmly established the significance of mitochondrial pathology as a central contributor to the onset of skeletal muscle atrophy in individuals with diabetes.Howev...Over the course of several decades,robust research has firmly established the significance of mitochondrial pathology as a central contributor to the onset of skeletal muscle atrophy in individuals with diabetes.However,the specific intricacies governing this process remain elusive.Extensive evidence highlights that individuals with diabetes regularly confront the severe consequences of skeletal muscle degradation.Deciphering the sophisticated mechanisms at the core of this pathology requires a thorough and meticulous exploration into the nuanced factors intricately associated with mitochondrial dysfunction.展开更多
Previous studies demonstrate an accumulation of transferrin and transferrin receptor 1(TfR1) in regenerating peripheral nerves.However, the expression and function of transferrin and TfR1 in the denervated skeletal mu...Previous studies demonstrate an accumulation of transferrin and transferrin receptor 1(TfR1) in regenerating peripheral nerves.However, the expression and function of transferrin and TfR1 in the denervated skeletal muscle remain poorly understood.In this study, a mouse model of denervation was produced by complete tear of the left brachial plexus nerve.RNA-sequencing revealed that transferrin expression in the denervated skeletal muscle was upregulated, while TfR1 expression was downregulated.We also investigated the function of TfR1 during development and in adult skeletal muscles in mice with inducible deletion or loss of TfR1.The ablation of TfR1 in skeletal muscle in early development caused severe muscular atrophy and early death.In comparison, deletion of TfR1 in adult skeletal muscles did not affect survival or glucose metabolism, but caused skeletal muscle atrophy and motor functional impairment, similar to the muscular atrophy phenotype observed after denervation.These findings suggest that TfR1 plays an important role in muscle development and denervation-induced muscular atrophy.This study was approved by the Institutional Animal Care and Use Committee of Beijing Institute of Basic Medical Sciences, China(approval No.SYXK 2017-C023) on June 1, 2018.展开更多
Sufficient clinical evidence suggests that the damage caused by ischemic stroke to the body occurs not only in the acute phase but also during the recovery period,and that the latter has a greater impact on the long-t...Sufficient clinical evidence suggests that the damage caused by ischemic stroke to the body occurs not only in the acute phase but also during the recovery period,and that the latter has a greater impact on the long-term prognosis of the patient.However,current stroke studies have typically focused only on lesions in the central nervous system,ignoring secondary damage caused by this disease.Such a phenomenon arises from the slow progress of pathophysiological studies examining the central nervous system.Further,the appropriate therapeutic time window and benefits of thrombolytic therapy are still controversial,leading scholars to explore more pragmatic intervention strategies.As treatment measures targeting limb symptoms can greatly improve a patient’s quality of life,they have become a critical intervention strategy.As the most vital component of the limbs,skeletal muscles have become potential points of concern.Despite this,to the best of our knowledge,there are no comprehensive reviews of pathophysiological changes and potential treatments for post-stroke skeletal muscle.The current review seeks to fill a gap in the current understanding of the pathological processes and mechanisms of muscle wasting atrophy,inflammation,neuroregeneration,mitochondrial changes,and nutritional dysregulation in stroke survivors.In addition,the challenges,as well as the optional solutions for individualized rehabilitation programs for stroke patients based on motor function are discussed.展开更多
Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is ...Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is considerable heterogeneity,including clinical presentation,progression,and the underlying triggers for disease initiation.Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations,it has become apparent that overt disease is preceded by a prodromal phase,possibly in years,where compensatory mechanisms delay symptom onset.Since 85-90%of amyotrophic lateral sclerosis is sporadic,there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration.Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease.Skeletal muscle,including the neuromuscular junction,manifests abnormalities at the earliest stages of the disease,before motor neuron loss,making it a promising source for identifying biomarkers of the prodromal phase.The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time.The advent of“omics”technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle,ranging from coding and non-coding RNAs to proteins and metabolites.This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms.A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease.There are two major goals of this review.The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity,evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages,and evidence of progressive change during disease progression.The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression,and as such,their potential as therapeutic targets in amyotrophic lateral sclerosis.展开更多
We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect ...We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect of 4-AP is unknown in nerve transection,gap,and grafting models.To evaluate and compare the functional recovery,nerve morphology,and muscle atrophy,we used a novel stepwise nerve transection with gluing(STG),as well as 7-mm irreparable nerve gap(G-7/0)and 7-mm isografting in 5-mm gap(G-5/7)models in the absence and presence of 4-AP treatment.Following surgery,sciatic functional index was determined wee kly to evaluate the direct in vivo global motor functional recovery.After 12 weeks,nerves were processed for whole-mount immunofluorescence imaging,and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber crosssectional area and minimal Feret's diameter.Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model.4-AP did not affect the sciatic functional index recovery in any model.Compared to STG,nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting.While muscle weight,cross-sectional area,and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7,4-AP treatment significantly increased right TA muscle mass,cross-sectional area,and minimal Feret's diameter in G-7/0 model.These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap,and 4-AP exerts diffe rential effects on functional recove ry and muscle atrophy.展开更多
Denervation-induced skeletal muscle atrophy can potentially cause the decline in the quality of life of patients and an increased risk of mortality.Complex pathophysiological mechanisms with dynamic alterations have b...Denervation-induced skeletal muscle atrophy can potentially cause the decline in the quality of life of patients and an increased risk of mortality.Complex pathophysiological mechanisms with dynamic alterations have been documented in skeletal muscle atrophy resulting from innervation loss.Hence,an in-depth comprehension of the key mechanisms and molecules governing skeletal muscle atrophy at varying stages,along with targeted treatment and protection,becomes essential for effective atrophy management.Our preliminary research categorizes the skeletal muscle atrophy process into four stages using microarray analysis.This review extensively discusses the pathways and molecules potentially implicated in regulating the four stages of denervation and muscle atrophy.Notably,drugs targeting the reactivare oxygen species stage and the inflammation stage assume critical roles.Timely intervention during the initial atrophy stages can expedite protection against skeletal muscle atrophy.Additionally,pharmaceutical intervention in the ubiquitin-proteasome pathway associated with atrophy and autophagy lysosomes can effectively slow down skeletal muscle atrophy.Key molecules within this stage encompass MuRF1,MAFbx,LC3II,p62/SQSTM1,etc.This review also compiles a profile of drugs with protective effects against skeletal muscle atrophy at distinct postdenervation stages,thereby augmenting the evidence base for denervation-induced skeletal muscle atrophy treatment.展开更多
Objective:To find the key targets of muscle atrophy after spinal cord injury(SCI)were excavated,to construct the lncRNA-miRNA-mRNA regulatory network based on bioinformatics analysis,and to verify the expression chang...Objective:To find the key targets of muscle atrophy after spinal cord injury(SCI)were excavated,to construct the lncRNA-miRNA-mRNA regulatory network based on bioinformatics analysis,and to verify the expression changes of key regulatory networks in muscle atrophy after SCI by animal experiments,so as to seek new research directions for the pathogenesis and treatment of muscle atrophy after SCI.Methods:The GSE21497 data set was downloaded from the GEO database for differential expression gene screening and WGCNA treatment.Combined with the online prediction database,key mRNAs were screened out.GO and KEGG enrichment analyses of key mRNAs were performed using the DAVID database to construct the lncRNA-miRNA-mRNA regulatory network.The key regulatory genes were selected and then verified by RT-qPCR.Results:A total of 1405 differentially expressed genes were screened,and 30 key mRNAs were predicted by the WGCNA and online database.GO and KEGG enrichment analyses showed that it was mainly enriched in the functions of neuron regeneration,protection,signal transmission,the HIF signaling pathway,PD-L1 expression and the PD-1 checkpoint pathway.Four key regulatory networks were identified(LINC00410/miR-17-5p/KCNK10,LINC00410/miR-17-5p/PCDHA3,LINC00410/miR-20b-5p/KCNK10,LINC00410/miR-20b-5p/PCDHA3).The results of RT-qPCR showed that,compared with the control group,the expression of miR-17-5p and miR-20b-5p in the observation group increased,and the expression of KCNK10 and PCDHA3 decreased.Conclusions:MiR-17-5p,miR-20b-5p,KCNK10,and PCDHA3 may play an important regulatory role in the regeneration,protection,and signal transmission of neurons,which is expected to become a new target for the diagnosis and treatment of muscle atrophy after SCI.展开更多
As a key coordinator of metabolism,AMP-activated protein kinase(AMPK)is vitally involved in skeletal muscle maintenance.AMPK exerts its cellular effects through its function as a serine/threonine protein kinase by reg...As a key coordinator of metabolism,AMP-activated protein kinase(AMPK)is vitally involved in skeletal muscle maintenance.AMPK exerts its cellular effects through its function as a serine/threonine protein kinase by regulating many downstream targets and plays important roles in the development and growth of skeletal muscle.AMPK is activated by phosphorylation and exerts its function as a kinase in many processes,including synthesis and degradation of proteins,mitochondrial biogenesis,glucose uptake,and fatty acid and cholesterol metabolism.Skeletal muscle atrophy is a result of various diseases or disorders and is characterized by a decrease in muscle mass.The pathogenesis and therapeutic strategies of skeletal muscle atrophy are still under investigation.In this review,we discuss the role of AMPK in skeletal muscle metabolism and atrophy.We also discuss targeting AMPK for skeletal muscle treatment,including exercise,AMPK activators including 5-amino-4-imidazolecarboxamide ribonucleoside and metformin,and low-level lasers.These studies show the important roles of AMPK in regulating muscle metabolism and function;thus,the treatment of skeletal muscle atrophy needs to take into account the roles of AMPK.展开更多
The depressed protein synthetic response,a phenomenon termed anabolic resistance,has been shown to be involved in muscle wasting induced by cancer cachexia.Moreover,a positive relationship between the protein syntheti...The depressed protein synthetic response,a phenomenon termed anabolic resistance,has been shown to be involved in muscle wasting induced by cancer cachexia.Moreover,a positive relationship between the protein synthetic rate and intracellular glutamine(GLN)concentration has been found in skeletal muscles.This study investigated the effects of neuromuscular electrical stimulation(ES)and GLN administration on muscle wasting and GLN metabolism in colon-26(C-26)tumor-bearing mice.CD2F1 mice were divided into 8 groups:control(CNT),CNT+ES,CNT+GLN,CNT+ES+GLN,C-26,C-26+ES,C-26+GLN,C-26+ES+GLN.Cancer cachexia was induced by subcutaneous injection of C-26 cells and developed for four weeks.ES was performed on the left plantar flexor muscles every other day,and GLN(1 g/kg)was administered daily intraperitoneally starting one day after the C-26 injection.Tumor-free body mass and fast-twitch gastrocnemius(Gas)muscle weight were lower in the C-26 group than in the CNT group(-19%and-17%,respectively).Neither ES training nor GLN administration,alone or in combination,ameliorated the loss of Gas muscle weight in the C-26 mice.However,ES training in combination with GLN administration inhibited the increased expression of GLN synthetase(GS)in the C-26 muscles.Thus,it is likely that GLN plays a critical role in muscle protein metabolism and,therefore,can be targeted as a tentative treatment of cancer cachexia.展开更多
Purpose: The objective of the present study was to determine whether a denervated muscle extract(DmEx) could stimulate satellite cell response in denervated muscle.Methods: Wistar rats were divided into 4 groups: norm...Purpose: The objective of the present study was to determine whether a denervated muscle extract(DmEx) could stimulate satellite cell response in denervated muscle.Methods: Wistar rats were divided into 4 groups: normal rats, normal rats treated with DmEx, denervated rats, and denervated rats treated with DmEx. The soleus muscles were examined using immunohistochemical techniques for proliferating cell nuclear antigen, desmin, and myogenic differentiation antigen(MyoD), and electron microscopy was used for analysis of the satellite cells.Results: The results indicate that while denervation causes activation of satellite cells, DmEx also induces myogenic differentiation of cells localized in the interstitial space and the formation of new muscle fibers. Although DmEx had a similar effect in nature on innervated and denervated muscles, this response was of greater magnitude in denervated vs. intact muscles.Conclusion: Our study shows that treatment of denervated rats with DmEx potentiates the myogenic response in atrophic denervated muscles.展开更多
Delay of axon regeneration after peripheral nerve injury usually leads to progressive muscle atrophy and poor functional recovery. The Wnt/β-catenin signaling pathway is considered to be one of the main molecular mec...Delay of axon regeneration after peripheral nerve injury usually leads to progressive muscle atrophy and poor functional recovery. The Wnt/β-catenin signaling pathway is considered to be one of the main molecular mechanisms that lead to skeletal muscle atrophy in the elderly. We hold the hypothesis that the innervation of target muscle can be promoted by accelerating axon regeneration and decelerating muscle cell degeneration so as to improve functional recovery of skeletal muscle following peripheral nerve injury. This process may be associated with the Wnt/β-catenin signaling pathway. Our study designed in vitro cell models to simulate myelin regeneration and muscle atrophy. We investigated the effects of SB216763, a glycogen synthase kinase 3 beta inhibitor, on the two major murine cell lines RSC96 and C2C12 derived from Schwann cells and muscle satellite cells. The results showed that SB216763 stimulated the Schwann cell migra- tion and myotube contraction. Quantitative polymerase chain reaction results demonstrated that myelin related genes, myelin associated glycoprotein and cyclin-D1, muscle related gene myogenin and endplate-associated gene nicotinic acetylcholine receptors levels were stimulated by SB216763. Immunocytochemical staining revealed that the expressions of ^-catenin in the RSC96 and C2C12 cytosolic and nuclear compartments were increased in the SB216763-treated cells. These findings confirm that the glycogen synthase kinase 3 beta in- hibitor, SB216763, promoted the myelination and myotube differentiation through the Wnt/β-catenin signaling pathway and contributed to nerve remyelination and reduced denervated muscle atrophy after peripheral nerve injury.展开更多
BACKGROUND Muscular atrophy is the basic defect of neurogenic clubfoot.Muscle atrophy of clubfoot needs more scientific and reasonable imaging measurement parameters to evaluate.The Hippo pathway and myostatin pathway...BACKGROUND Muscular atrophy is the basic defect of neurogenic clubfoot.Muscle atrophy of clubfoot needs more scientific and reasonable imaging measurement parameters to evaluate.The Hippo pathway and myostatin pathway may be directly correlated in myogenesis.In this study,we will use congenital neurogenic clubfoot muscle atrophy model to verify in vivo.Further,the antagonistic mechanism of TAZ on myostatin was studied in the C2C12 cell differentiation model.AIM To identify muscle atrophy in fetal neurogenic clubfoot by ultrasound imaging and detect the expression of TAZ and myostatin in gastrocnemius muscle.To elucidate the possible mechanisms by which TAZ antagonizes myostatin-induced atrophy in an in vitro cell model.METHODS Muscle atrophy in eight cases of fetal unilateral clubfoot with nervous system abnormalities was identified by 2D and 3D ultrasound.Western blotting and immunostaining were performed to detect expression of myostatin and TAZ.TAZ overexpression in C2C12 myotubes and the expression of associated proteins were analyzed by western blotting.RESULTS The maximum cross-sectional area of the fetal clubfoot on the varus side was reduced compared to the contralateral side.Myostatin was elevated in the atrophied gastrocnemius muscle,while TAZ expression was decreased.They were negatively correlated.TAZ overexpression reversed the diameter reduction of the myotube,downregulated phosphorylated Akt,and increased the expression of forkhead box O4 induced by myostatin.CONCLUSION Ultrasound can detect muscle atrophy of fetal clubfoot.TAZ and myostatin are involved in the pathological process of neurogenic clubfoot muscle atrophy.TAZ antagonizes myostatin-induced myotube atrophy,potentially through regulation of the Akt/forkhead box O4 signaling pathway.展开更多
Apoptosis is necessary for maintaining the integrity of proliferative tissues, such as epithelial cells of the gastrointestinal system. The role of apoptosis in post mitotic tissues, such as skeletal muscle, is less w...Apoptosis is necessary for maintaining the integrity of proliferative tissues, such as epithelial cells of the gastrointestinal system. The role of apoptosis in post mitotic tissues, such as skeletal muscle, is less well defined. Apoptosis during muscle atrophy occurs in both myonuclei and other muscle cell types. Apoptosis of myonuclei likely contributes to the loss of muscle mass, but the mechanisms underlying this process are largely unknown. Caspase-dependent as well as -independent pathways have been implicated and the mode by which atrophy is induced likely determines the apoptotic mechanisms that are utilized. It remains to be determined whether a decrease in apoptosis will alleviate atrophy and distinct research strategies may be required for different causes of skeletal muscle loss.展开更多
OBJECTIVE Skeletal muscle undergoes rapid and profound atrophy in response to decreased mechanical loading,e.g.,limb immobilization and bed rest.Phosphatidylinositol 3 kinase(PI3K)/Akt signaling pathway is critical fo...OBJECTIVE Skeletal muscle undergoes rapid and profound atrophy in response to decreased mechanical loading,e.g.,limb immobilization and bed rest.Phosphatidylinositol 3 kinase(PI3K)/Akt signaling pathway is critical for regulating the balance between protein synthesis and degradation during disuse/inactivity-induced muscle atrophy.The present study aimed to investigate whether natural product Icaritin(ICT)required PI3K/Akt signaling to exert counteractive effect on skeletal muscle atrophy following mechanical unloading.METHODS Two oral dosages of ICT(80and 120mg·kg-1·d-1)were administrated daily to adult male rats with or without daily injection of PI3K/Akt signaling inhibitor wortmannin(15μg·kg-1·d-1)during 28-d hindlimb suspension(HS).Ex vivo muscle functional testing,histological and immunohistochemical analysis were performed to determine the changes of soleus muscle function,mean muscle fiber cross-sectional area(CSA)and fiber type distribution.Western blot and real-time PCR analysis were also performed to evaluate the protein or mRNA expression of the markers involved in PI3K/Akt signaling pathway.RESULTS After 28-d HS,soleus muscle underwent profound muscle atrophy(-52.7% muscle mass vs.pre-HS baseline).The high dose ICT treatment significantly attenuated the decreases in soleus muscle mass(+22.6% vs.HS),muscle fiber CSA(+52.8% vs.HS),as well as the muscle functional testing parameters during the unloading.Molecularly,the high dose ICT treatment significantly attenuated the decreases in protein synthesis markers at protein levels(phosphorylation of Akt and its downstream proteins)during the unloading,whereas the increases in protein degradation markers at mRNA(atrogin-1and MuRF-1)and protein(nuclear FOXO1 and FOXO3a)levels during the unloading were significantly attenuated by the high dose ICT treatment.The low dose ICT treatment moderately attenuated the above changes induced by the unloading.Mechanistically,Wortmannin could abolish the above effects of ICT.CONCLUSION ICT requires participation of PI3K/Akt signaling to counteract skeletal muscle atrophy following mechanical unloading in a dose-dependent manner.展开更多
Background:Exercise is beneficial for muscle atrophy.Peroxisome proliferator-activated receptor gamma(PPARγ) and microRNA-29 b(miR-29 b) have been reported to be responsible for angiotensinⅡ(AngⅡ)-induced muscle at...Background:Exercise is beneficial for muscle atrophy.Peroxisome proliferator-activated receptor gamma(PPARγ) and microRNA-29 b(miR-29 b) have been reported to be responsible for angiotensinⅡ(AngⅡ)-induced muscle atrophy.However,it is unclear whether exercise can protect AngⅡ-induced muscle atrophy by targeting PPARγ/miR-29 b.Methods:Skeletal muscle atrophy in both the control group and the run group was established by AngⅡ infusion;after 1 week of exercise training,the mice were sacrificed,and muscle weight was determined.Myofiber size was measured by hematoxylin-eosin and wheat-germ agglutinin staining.Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining.The expression level of muscle atrogenes,including F-box only protein 32(FBXO32,also called Atrogin-1) and muscle-specific RING-finger 1(MuRF-1),the phosphorylation level of protein kinase B(PKB,also called AKT)/forkhead box 03 A(FOX03 A)/mammalian target of rapamycin(mTOR) pathway proteins,the expression level of PPARγ and apoptosis-related proteins,including B-cell lymphoma-2(Bcl-2),Bcl-2-associated X(Bax),cysteine-aspartic acid protease 3(caspase-3),and cleaved-caspase-3,were determined by western blot.The expression level of miR-29 b was checked by reversetranscription quantitative polymerase chain reaction.A PPARγ inhibitor(T0070907) or adeno-associated virus serotype-8(AAV8)-mediated miR-29 b overexpression was used to demonstrate whether PPARγ activation or miR-29 b inhibition mediates the beneficial effects of exercise in AngⅡ-induced muscle atrophy.Results:Exercise can significantly attenuate AngⅡ-induced muscle atrophy,which is demonstrated by increased skeletal muscle weight,cross-sectional area of myofiber,and activation of AKT/mTOR signaling and by decreased atrogenes expressions and apoptosis.In AngⅡ-induced muscle atrophy mice models,PPARγ was elevated whereas miR-29 b was decreased by exercise.The protective effects of exercise in AngⅡ-induced muscle atrophy were inhibited by a PPARγ inhibitor(T0070907) or adeno-associated virus serotype-8(AAV8)-mediated miR-29 b overexpression.Conclusion:Exercise attenuates AngⅡ-induced muscle atrophy by activation of PPARγ and suppression of miR-29 b.展开更多
Nerve injury commonly contributes to irreversible functional impairment, reconstruction of the function of muscle is big challenge. In denervated skeletal muscle, therapid expression of MyoD mRNA and protein also occu...Nerve injury commonly contributes to irreversible functional impairment, reconstruction of the function of muscle is big challenge. In denervated skeletal muscle, therapid expression of MyoD mRNA and protein also occurs during early postdenervation, which suggested that the function of denervation-induced MyoD may be to prevent denervation-induced skeletal muscle atrophy. However, the detail mechanism is not clear. Therefore, in this study, we established a stable-transfected MyoD L6 cell line. After the operation for cutting the rats’ tibial nerve, the MyoD-L6 cells were injected in the gastrocnemius, the function of the gastronemius was monitored. It was found that injected the MyoD-L6 cells could attenuate the muscle atrophy and dysfunction. Therefore, overexpression of MyoD could serve as a new therapy strategy to cure denervation-induced dysfunction of skeletal muscle.展开更多
Myasthenia gravis (MG) is an autoimmune disorder involving the neuromuscular junction that frequently affects the extra-ocular muscles (EOMs). It has been described as a very rare cause of bilateral EOM atrophy, but h...Myasthenia gravis (MG) is an autoimmune disorder involving the neuromuscular junction that frequently affects the extra-ocular muscles (EOMs). It has been described as a very rare cause of bilateral EOM atrophy, but histological analysis of such cases is lacking. A 66-year-old man presented with two months of right eyelid drooping and vertical diplopia. Examination showed bilateral ophthalmoparesis and complete right ptosis. The remainder of his exam was normal, and an MRI showed small EOMs. Acetylcholine receptor antibodies were elevated, establishing the diagnosis of MG. Oral corticosteroids and pyridostigmine followed by azathioprine improved his ptosis, but not his ophthalmoparesis. One year later he had surgical correction of his diplopia, and the resected superior rectus muscle showed complete replacement of EOM by connective tissue. MG can rarely cause bilateral EOM atrophy, which is characterized histologically by fibrosis in the muscle itself. Atrophy in the EOMs of a myasthenic patient may indicate a poor response to medical management alone.展开更多
AIM:To study the electromyogram and muscular pathological features of adult sp inal muscular atrophy(SMA4).METHODS:46 cases of SMA4 were evaluated based on cli nical,histopathology,enzyme histochemistry and ultrastruc...AIM:To study the electromyogram and muscular pathological features of adult sp inal muscular atrophy(SMA4).METHODS:46 cases of SMA4 were evaluated based on cli nical,histopathology,enzyme histochemistry and ultrastructure.RESULTS:A mean age of the patients with SMA4 was 38.7 years,clinical progressed was slowly.Clinic manifestations mainly appeared proximal muscular weakness and progressive muscul ar atrophy,and there was a relatively good prognosis.Laboratory found:one-fourt h of the disease had elevated serum creatine kinase levels.Eletromyogram reveale d neurogenic damages. The muscular pathological changes showed small groups of a trophy of denervation,ATPase reaction showed fibre-type grouping of renervation and hypertrophy in muscle fibers.CONCLUSION:Muscle biopsy was important;it coul d to help to establish to diagnose the disorder and provided available cases for gene study.展开更多
In treating patients with obstetric brachial plexus palsy,we noticed that denervated intrinsic muscles of the hand become irreversibly atrophic at a faster than denervated biceps.In a rat model of obstetric brachial p...In treating patients with obstetric brachial plexus palsy,we noticed that denervated intrinsic muscles of the hand become irreversibly atrophic at a faster than denervated biceps.In a rat model of obstetric brachial plexus palsy,denervated intrinsic musculature of the forepaw entered the irreversible atrophy far earlier than denervated biceps.In this study,isobaric tags for relative and absolute quantitation were examined in the intrinsic musculature of forepaw and biceps on denervated and normal sides at 3 and 5 weeks to identify dysregulated proteins.Enrichment of pathways mapped by those proteins was analyzed by Kyoto Encyclopedia of Genes and Genomes analysis.At 3 weeks,119 dysregulated proteins in denervated intrinsic musculature of the forepaw were mapped to nine pathways for muscle regulation,while 67 dysregulated proteins were mapped to three such pathways at 5 weeks.At 3 weeks,27 upregulated proteins were mapped to five pathways involving inflammation and apoptosis,while two upregulated proteins were mapped to one such pathway at 5 weeks.At 3 and 5 weeks,53 proteins from pathways involving regrowth and differentiation were downregulated.At 3 weeks,64 dysregulated proteins in denervated biceps were mapped to five pathways involving muscle regulation,while,five dysregulated proteins were mapped to three such pathways at 5 weeks.One protein mapped to inflammation and apoptotic pathways was upregulated from one pathway at 3 weeks,while three proteins were downregulated from two other pathways at 5 weeks.Four proteins mapped to regrowth and differentiation pathways were upregulated from three pathways at 3 weeks,while two proteins were downregulated in another pathway at 5 weeks.These results implicated inflammation and apoptosis as critical factors aggravating atrophy of denervated intrinsic muscles of the hand during obstetric brachial plexus palsy.All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Fudan University,China(approval No.DF-325)in January 2015.展开更多
The purpose of this study was to investigate the intensity-specific regenerative effects of microcurrent therapy on gastrocnemius muscle atrophy induced by cast-immobilization in rabbits. Fifteen rabbits were randomly...The purpose of this study was to investigate the intensity-specific regenerative effects of microcurrent therapy on gastrocnemius muscle atrophy induced by cast-immobilization in rabbits. Fifteen rabbits were randomly allocated to 3 groups after cast removal: cast-immobilization and sham microcurrent therapy for 2 weeks(group 1); castimmobilization and microcurrent therapy(25 μA) for 2 weeks(group 2); cast-immobilization and microcurrent therapy(5,000 μA) for 2 weeks(group 3). Clinical parameters [calf circumference, compound muscle action potential(CMAP) of the tibial nerve, thickness of gastrocnemius muscle], cross sectional area of gastrocnemius muscle fibres,and immunohistochemistry was evaluated. The clinical parameters representing mean atrophic changes in group 2 were significantly lower than those in group 3. The cross sectional area of the gastrocnemius muscle fibres and immunohistochemical parameters in group 2 were significantly greater than those in group 3. The results showed that low-intensity microcurrent therapy can more effectively promote regeneration in atrophied gastrocnemius muscle than high-intensity microcurrent therapy.展开更多
基金the Foundation of State Key Laboratory of Component-based Chinese Medicine,No.CBCM2023107National Natural Science Foundation of China,No.81901853Specially Funded Scientific Research Project of the Fourth Affiliated Hospital of Harbin Medical University,No.HYDSYTB202126.
文摘Over the course of several decades,robust research has firmly established the significance of mitochondrial pathology as a central contributor to the onset of skeletal muscle atrophy in individuals with diabetes.However,the specific intricacies governing this process remain elusive.Extensive evidence highlights that individuals with diabetes regularly confront the severe consequences of skeletal muscle degradation.Deciphering the sophisticated mechanisms at the core of this pathology requires a thorough and meticulous exploration into the nuanced factors intricately associated with mitochondrial dysfunction.
基金supported by the National Natural Science Foundation of China, Nos.31770929(to HTW), 31522029(to HTW), 81902847(to HHY)the Beijing Municipal Science and Technology Commission of China, Nos.Z181100001518001(to HTW), Z161100000216154(to HTW)。
文摘Previous studies demonstrate an accumulation of transferrin and transferrin receptor 1(TfR1) in regenerating peripheral nerves.However, the expression and function of transferrin and TfR1 in the denervated skeletal muscle remain poorly understood.In this study, a mouse model of denervation was produced by complete tear of the left brachial plexus nerve.RNA-sequencing revealed that transferrin expression in the denervated skeletal muscle was upregulated, while TfR1 expression was downregulated.We also investigated the function of TfR1 during development and in adult skeletal muscles in mice with inducible deletion or loss of TfR1.The ablation of TfR1 in skeletal muscle in early development caused severe muscular atrophy and early death.In comparison, deletion of TfR1 in adult skeletal muscles did not affect survival or glucose metabolism, but caused skeletal muscle atrophy and motor functional impairment, similar to the muscular atrophy phenotype observed after denervation.These findings suggest that TfR1 plays an important role in muscle development and denervation-induced muscular atrophy.This study was approved by the Institutional Animal Care and Use Committee of Beijing Institute of Basic Medical Sciences, China(approval No.SYXK 2017-C023) on June 1, 2018.
基金supported by the National Natural Science Foundation of China for Young Scientists,No.82104732(to RY)Xinglin Scholar Project of Chengdu University of Traditional Chinese Medicine,No.BSH2020022(to RY)the Open Research Fund of Chengdu University of Traditional Chinese Medicine Key Laboratory of Systematic Research of Distinctive Chinese Medicine Resources in Southwest China,No.2020XSGG002(to NZ)。
文摘Sufficient clinical evidence suggests that the damage caused by ischemic stroke to the body occurs not only in the acute phase but also during the recovery period,and that the latter has a greater impact on the long-term prognosis of the patient.However,current stroke studies have typically focused only on lesions in the central nervous system,ignoring secondary damage caused by this disease.Such a phenomenon arises from the slow progress of pathophysiological studies examining the central nervous system.Further,the appropriate therapeutic time window and benefits of thrombolytic therapy are still controversial,leading scholars to explore more pragmatic intervention strategies.As treatment measures targeting limb symptoms can greatly improve a patient’s quality of life,they have become a critical intervention strategy.As the most vital component of the limbs,skeletal muscles have become potential points of concern.Despite this,to the best of our knowledge,there are no comprehensive reviews of pathophysiological changes and potential treatments for post-stroke skeletal muscle.The current review seeks to fill a gap in the current understanding of the pathological processes and mechanisms of muscle wasting atrophy,inflammation,neuroregeneration,mitochondrial changes,and nutritional dysregulation in stroke survivors.In addition,the challenges,as well as the optional solutions for individualized rehabilitation programs for stroke patients based on motor function are discussed.
基金supported by NIH Grants R01NS092651 and R21NS111275-01the Department of Veterans Affairs,BX001148 and BX005899(to PHK)。
文摘Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is considerable heterogeneity,including clinical presentation,progression,and the underlying triggers for disease initiation.Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations,it has become apparent that overt disease is preceded by a prodromal phase,possibly in years,where compensatory mechanisms delay symptom onset.Since 85-90%of amyotrophic lateral sclerosis is sporadic,there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration.Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease.Skeletal muscle,including the neuromuscular junction,manifests abnormalities at the earliest stages of the disease,before motor neuron loss,making it a promising source for identifying biomarkers of the prodromal phase.The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time.The advent of“omics”technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle,ranging from coding and non-coding RNAs to proteins and metabolites.This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms.A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease.There are two major goals of this review.The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity,evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages,and evidence of progressive change during disease progression.The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression,and as such,their potential as therapeutic targets in amyotrophic lateral sclerosis.
基金supported by grants from the National Institutes of Health,USA(No.K08 AR060164-01A)Department of Defense,USA(Nos.W81XWH-16-1-0725 and W81XWH-19-1-0773)in addition to institutional support from the Pennsylvania State University College of Medicine。
文摘We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect of 4-AP is unknown in nerve transection,gap,and grafting models.To evaluate and compare the functional recovery,nerve morphology,and muscle atrophy,we used a novel stepwise nerve transection with gluing(STG),as well as 7-mm irreparable nerve gap(G-7/0)and 7-mm isografting in 5-mm gap(G-5/7)models in the absence and presence of 4-AP treatment.Following surgery,sciatic functional index was determined wee kly to evaluate the direct in vivo global motor functional recovery.After 12 weeks,nerves were processed for whole-mount immunofluorescence imaging,and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber crosssectional area and minimal Feret's diameter.Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model.4-AP did not affect the sciatic functional index recovery in any model.Compared to STG,nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting.While muscle weight,cross-sectional area,and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7,4-AP treatment significantly increased right TA muscle mass,cross-sectional area,and minimal Feret's diameter in G-7/0 model.These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap,and 4-AP exerts diffe rential effects on functional recove ry and muscle atrophy.
基金supported by the National Natural Science Foundation of China(Grant No.32200940)Science and Technology Bureau of Nantong(Grant Nos.JC2020101,JC2021085)Municipal Health Commission of Nantong(Grant No.MA2020019).
文摘Denervation-induced skeletal muscle atrophy can potentially cause the decline in the quality of life of patients and an increased risk of mortality.Complex pathophysiological mechanisms with dynamic alterations have been documented in skeletal muscle atrophy resulting from innervation loss.Hence,an in-depth comprehension of the key mechanisms and molecules governing skeletal muscle atrophy at varying stages,along with targeted treatment and protection,becomes essential for effective atrophy management.Our preliminary research categorizes the skeletal muscle atrophy process into four stages using microarray analysis.This review extensively discusses the pathways and molecules potentially implicated in regulating the four stages of denervation and muscle atrophy.Notably,drugs targeting the reactivare oxygen species stage and the inflammation stage assume critical roles.Timely intervention during the initial atrophy stages can expedite protection against skeletal muscle atrophy.Additionally,pharmaceutical intervention in the ubiquitin-proteasome pathway associated with atrophy and autophagy lysosomes can effectively slow down skeletal muscle atrophy.Key molecules within this stage encompass MuRF1,MAFbx,LC3II,p62/SQSTM1,etc.This review also compiles a profile of drugs with protective effects against skeletal muscle atrophy at distinct postdenervation stages,thereby augmenting the evidence base for denervation-induced skeletal muscle atrophy treatment.
基金National Natural Science Foundation of China(No.81960417)Guangxi Natural Science Foundation Project(No.2018GXNSFAA050033)+1 种基金Guangxi Science and Technology Key R&D Project(No.Guike AB20159027)Guangxi Natural Science Foundation Youth Fund Project(No.2022GXNSFBA035545)。
文摘Objective:To find the key targets of muscle atrophy after spinal cord injury(SCI)were excavated,to construct the lncRNA-miRNA-mRNA regulatory network based on bioinformatics analysis,and to verify the expression changes of key regulatory networks in muscle atrophy after SCI by animal experiments,so as to seek new research directions for the pathogenesis and treatment of muscle atrophy after SCI.Methods:The GSE21497 data set was downloaded from the GEO database for differential expression gene screening and WGCNA treatment.Combined with the online prediction database,key mRNAs were screened out.GO and KEGG enrichment analyses of key mRNAs were performed using the DAVID database to construct the lncRNA-miRNA-mRNA regulatory network.The key regulatory genes were selected and then verified by RT-qPCR.Results:A total of 1405 differentially expressed genes were screened,and 30 key mRNAs were predicted by the WGCNA and online database.GO and KEGG enrichment analyses showed that it was mainly enriched in the functions of neuron regeneration,protection,signal transmission,the HIF signaling pathway,PD-L1 expression and the PD-1 checkpoint pathway.Four key regulatory networks were identified(LINC00410/miR-17-5p/KCNK10,LINC00410/miR-17-5p/PCDHA3,LINC00410/miR-20b-5p/KCNK10,LINC00410/miR-20b-5p/PCDHA3).The results of RT-qPCR showed that,compared with the control group,the expression of miR-17-5p and miR-20b-5p in the observation group increased,and the expression of KCNK10 and PCDHA3 decreased.Conclusions:MiR-17-5p,miR-20b-5p,KCNK10,and PCDHA3 may play an important regulatory role in the regeneration,protection,and signal transmission of neurons,which is expected to become a new target for the diagnosis and treatment of muscle atrophy after SCI.
基金supported by the Natural Science Foundation of China(Grant No.32071517,82072106)the Natural Science Basic Research Plan in Shaanxi Province of China(Grant No.2020JM-100).
文摘As a key coordinator of metabolism,AMP-activated protein kinase(AMPK)is vitally involved in skeletal muscle maintenance.AMPK exerts its cellular effects through its function as a serine/threonine protein kinase by regulating many downstream targets and plays important roles in the development and growth of skeletal muscle.AMPK is activated by phosphorylation and exerts its function as a kinase in many processes,including synthesis and degradation of proteins,mitochondrial biogenesis,glucose uptake,and fatty acid and cholesterol metabolism.Skeletal muscle atrophy is a result of various diseases or disorders and is characterized by a decrease in muscle mass.The pathogenesis and therapeutic strategies of skeletal muscle atrophy are still under investigation.In this review,we discuss the role of AMPK in skeletal muscle metabolism and atrophy.We also discuss targeting AMPK for skeletal muscle treatment,including exercise,AMPK activators including 5-amino-4-imidazolecarboxamide ribonucleoside and metformin,and low-level lasers.These studies show the important roles of AMPK in regulating muscle metabolism and function;thus,the treatment of skeletal muscle atrophy needs to take into account the roles of AMPK.
文摘The depressed protein synthetic response,a phenomenon termed anabolic resistance,has been shown to be involved in muscle wasting induced by cancer cachexia.Moreover,a positive relationship between the protein synthetic rate and intracellular glutamine(GLN)concentration has been found in skeletal muscles.This study investigated the effects of neuromuscular electrical stimulation(ES)and GLN administration on muscle wasting and GLN metabolism in colon-26(C-26)tumor-bearing mice.CD2F1 mice were divided into 8 groups:control(CNT),CNT+ES,CNT+GLN,CNT+ES+GLN,C-26,C-26+ES,C-26+GLN,C-26+ES+GLN.Cancer cachexia was induced by subcutaneous injection of C-26 cells and developed for four weeks.ES was performed on the left plantar flexor muscles every other day,and GLN(1 g/kg)was administered daily intraperitoneally starting one day after the C-26 injection.Tumor-free body mass and fast-twitch gastrocnemius(Gas)muscle weight were lower in the C-26 group than in the CNT group(-19%and-17%,respectively).Neither ES training nor GLN administration,alone or in combination,ameliorated the loss of Gas muscle weight in the C-26 mice.However,ES training in combination with GLN administration inhibited the increased expression of GLN synthetase(GS)in the C-26 muscles.Thus,it is likely that GLN plays a critical role in muscle protein metabolism and,therefore,can be targeted as a tentative treatment of cancer cachexia.
文摘Purpose: The objective of the present study was to determine whether a denervated muscle extract(DmEx) could stimulate satellite cell response in denervated muscle.Methods: Wistar rats were divided into 4 groups: normal rats, normal rats treated with DmEx, denervated rats, and denervated rats treated with DmEx. The soleus muscles were examined using immunohistochemical techniques for proliferating cell nuclear antigen, desmin, and myogenic differentiation antigen(MyoD), and electron microscopy was used for analysis of the satellite cells.Results: The results indicate that while denervation causes activation of satellite cells, DmEx also induces myogenic differentiation of cells localized in the interstitial space and the formation of new muscle fibers. Although DmEx had a similar effect in nature on innervated and denervated muscles, this response was of greater magnitude in denervated vs. intact muscles.Conclusion: Our study shows that treatment of denervated rats with DmEx potentiates the myogenic response in atrophic denervated muscles.
基金funded by the National Basic Research Program of China(973 Program),No.2014CB542201the National High Technology Research and Development Program of China(863 Program),No.SS2015AA020501the National Natural Science Foundation of China(General Program),No.31571235,31771322,31671248,31571236,31271284,31171150,81171146,31471144,30971526,31100860,31040043,31371210,and 81372044
文摘Delay of axon regeneration after peripheral nerve injury usually leads to progressive muscle atrophy and poor functional recovery. The Wnt/β-catenin signaling pathway is considered to be one of the main molecular mechanisms that lead to skeletal muscle atrophy in the elderly. We hold the hypothesis that the innervation of target muscle can be promoted by accelerating axon regeneration and decelerating muscle cell degeneration so as to improve functional recovery of skeletal muscle following peripheral nerve injury. This process may be associated with the Wnt/β-catenin signaling pathway. Our study designed in vitro cell models to simulate myelin regeneration and muscle atrophy. We investigated the effects of SB216763, a glycogen synthase kinase 3 beta inhibitor, on the two major murine cell lines RSC96 and C2C12 derived from Schwann cells and muscle satellite cells. The results showed that SB216763 stimulated the Schwann cell migra- tion and myotube contraction. Quantitative polymerase chain reaction results demonstrated that myelin related genes, myelin associated glycoprotein and cyclin-D1, muscle related gene myogenin and endplate-associated gene nicotinic acetylcholine receptors levels were stimulated by SB216763. Immunocytochemical staining revealed that the expressions of ^-catenin in the RSC96 and C2C12 cytosolic and nuclear compartments were increased in the SB216763-treated cells. These findings confirm that the glycogen synthase kinase 3 beta in- hibitor, SB216763, promoted the myelination and myotube differentiation through the Wnt/β-catenin signaling pathway and contributed to nerve remyelination and reduced denervated muscle atrophy after peripheral nerve injury.
文摘BACKGROUND Muscular atrophy is the basic defect of neurogenic clubfoot.Muscle atrophy of clubfoot needs more scientific and reasonable imaging measurement parameters to evaluate.The Hippo pathway and myostatin pathway may be directly correlated in myogenesis.In this study,we will use congenital neurogenic clubfoot muscle atrophy model to verify in vivo.Further,the antagonistic mechanism of TAZ on myostatin was studied in the C2C12 cell differentiation model.AIM To identify muscle atrophy in fetal neurogenic clubfoot by ultrasound imaging and detect the expression of TAZ and myostatin in gastrocnemius muscle.To elucidate the possible mechanisms by which TAZ antagonizes myostatin-induced atrophy in an in vitro cell model.METHODS Muscle atrophy in eight cases of fetal unilateral clubfoot with nervous system abnormalities was identified by 2D and 3D ultrasound.Western blotting and immunostaining were performed to detect expression of myostatin and TAZ.TAZ overexpression in C2C12 myotubes and the expression of associated proteins were analyzed by western blotting.RESULTS The maximum cross-sectional area of the fetal clubfoot on the varus side was reduced compared to the contralateral side.Myostatin was elevated in the atrophied gastrocnemius muscle,while TAZ expression was decreased.They were negatively correlated.TAZ overexpression reversed the diameter reduction of the myotube,downregulated phosphorylated Akt,and increased the expression of forkhead box O4 induced by myostatin.CONCLUSION Ultrasound can detect muscle atrophy of fetal clubfoot.TAZ and myostatin are involved in the pathological process of neurogenic clubfoot muscle atrophy.TAZ antagonizes myostatin-induced myotube atrophy,potentially through regulation of the Akt/forkhead box O4 signaling pathway.
基金Supported by NIH/NIA, No.AG20407 NIH/NIAMS, No. AR47577
文摘Apoptosis is necessary for maintaining the integrity of proliferative tissues, such as epithelial cells of the gastrointestinal system. The role of apoptosis in post mitotic tissues, such as skeletal muscle, is less well defined. Apoptosis during muscle atrophy occurs in both myonuclei and other muscle cell types. Apoptosis of myonuclei likely contributes to the loss of muscle mass, but the mechanisms underlying this process are largely unknown. Caspase-dependent as well as -independent pathways have been implicated and the mode by which atrophy is induced likely determines the apoptotic mechanisms that are utilized. It remains to be determined whether a decrease in apoptosis will alleviate atrophy and distinct research strategies may be required for different causes of skeletal muscle loss.
基金The project supported by National Natural Science Foundation of China(81201406)Direct Grant for Research,The Chinese University of Hong Kong(4054138)
文摘OBJECTIVE Skeletal muscle undergoes rapid and profound atrophy in response to decreased mechanical loading,e.g.,limb immobilization and bed rest.Phosphatidylinositol 3 kinase(PI3K)/Akt signaling pathway is critical for regulating the balance between protein synthesis and degradation during disuse/inactivity-induced muscle atrophy.The present study aimed to investigate whether natural product Icaritin(ICT)required PI3K/Akt signaling to exert counteractive effect on skeletal muscle atrophy following mechanical unloading.METHODS Two oral dosages of ICT(80and 120mg·kg-1·d-1)were administrated daily to adult male rats with or without daily injection of PI3K/Akt signaling inhibitor wortmannin(15μg·kg-1·d-1)during 28-d hindlimb suspension(HS).Ex vivo muscle functional testing,histological and immunohistochemical analysis were performed to determine the changes of soleus muscle function,mean muscle fiber cross-sectional area(CSA)and fiber type distribution.Western blot and real-time PCR analysis were also performed to evaluate the protein or mRNA expression of the markers involved in PI3K/Akt signaling pathway.RESULTS After 28-d HS,soleus muscle underwent profound muscle atrophy(-52.7% muscle mass vs.pre-HS baseline).The high dose ICT treatment significantly attenuated the decreases in soleus muscle mass(+22.6% vs.HS),muscle fiber CSA(+52.8% vs.HS),as well as the muscle functional testing parameters during the unloading.Molecularly,the high dose ICT treatment significantly attenuated the decreases in protein synthesis markers at protein levels(phosphorylation of Akt and its downstream proteins)during the unloading,whereas the increases in protein degradation markers at mRNA(atrogin-1and MuRF-1)and protein(nuclear FOXO1 and FOXO3a)levels during the unloading were significantly attenuated by the high dose ICT treatment.The low dose ICT treatment moderately attenuated the above changes induced by the unloading.Mechanistically,Wortmannin could abolish the above effects of ICT.CONCLUSION ICT requires participation of PI3K/Akt signaling to counteract skeletal muscle atrophy following mechanical unloading in a dose-dependent manner.
基金supported by grants from the National Key Research and Development Project(2020YFA0803800 to JL,2018YFE0113500 to JX)National Natural Science Foundation of China(82020108002 and 81911540486 to JX)+2 种基金Innovation Program of Shanghai Municipal Education Commission(2017-01-07-00-09-E00042 to JX)Science and Technology Commission of Shanghai Municipality(20DZ2255400 and 18410722200 to JX)the“Dawn”Program of the Shanghai Education Commission(19SG34 to JX).
文摘Background:Exercise is beneficial for muscle atrophy.Peroxisome proliferator-activated receptor gamma(PPARγ) and microRNA-29 b(miR-29 b) have been reported to be responsible for angiotensinⅡ(AngⅡ)-induced muscle atrophy.However,it is unclear whether exercise can protect AngⅡ-induced muscle atrophy by targeting PPARγ/miR-29 b.Methods:Skeletal muscle atrophy in both the control group and the run group was established by AngⅡ infusion;after 1 week of exercise training,the mice were sacrificed,and muscle weight was determined.Myofiber size was measured by hematoxylin-eosin and wheat-germ agglutinin staining.Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining.The expression level of muscle atrogenes,including F-box only protein 32(FBXO32,also called Atrogin-1) and muscle-specific RING-finger 1(MuRF-1),the phosphorylation level of protein kinase B(PKB,also called AKT)/forkhead box 03 A(FOX03 A)/mammalian target of rapamycin(mTOR) pathway proteins,the expression level of PPARγ and apoptosis-related proteins,including B-cell lymphoma-2(Bcl-2),Bcl-2-associated X(Bax),cysteine-aspartic acid protease 3(caspase-3),and cleaved-caspase-3,were determined by western blot.The expression level of miR-29 b was checked by reversetranscription quantitative polymerase chain reaction.A PPARγ inhibitor(T0070907) or adeno-associated virus serotype-8(AAV8)-mediated miR-29 b overexpression was used to demonstrate whether PPARγ activation or miR-29 b inhibition mediates the beneficial effects of exercise in AngⅡ-induced muscle atrophy.Results:Exercise can significantly attenuate AngⅡ-induced muscle atrophy,which is demonstrated by increased skeletal muscle weight,cross-sectional area of myofiber,and activation of AKT/mTOR signaling and by decreased atrogenes expressions and apoptosis.In AngⅡ-induced muscle atrophy mice models,PPARγ was elevated whereas miR-29 b was decreased by exercise.The protective effects of exercise in AngⅡ-induced muscle atrophy were inhibited by a PPARγ inhibitor(T0070907) or adeno-associated virus serotype-8(AAV8)-mediated miR-29 b overexpression.Conclusion:Exercise attenuates AngⅡ-induced muscle atrophy by activation of PPARγ and suppression of miR-29 b.
文摘Nerve injury commonly contributes to irreversible functional impairment, reconstruction of the function of muscle is big challenge. In denervated skeletal muscle, therapid expression of MyoD mRNA and protein also occurs during early postdenervation, which suggested that the function of denervation-induced MyoD may be to prevent denervation-induced skeletal muscle atrophy. However, the detail mechanism is not clear. Therefore, in this study, we established a stable-transfected MyoD L6 cell line. After the operation for cutting the rats’ tibial nerve, the MyoD-L6 cells were injected in the gastrocnemius, the function of the gastronemius was monitored. It was found that injected the MyoD-L6 cells could attenuate the muscle atrophy and dysfunction. Therefore, overexpression of MyoD could serve as a new therapy strategy to cure denervation-induced dysfunction of skeletal muscle.
文摘Myasthenia gravis (MG) is an autoimmune disorder involving the neuromuscular junction that frequently affects the extra-ocular muscles (EOMs). It has been described as a very rare cause of bilateral EOM atrophy, but histological analysis of such cases is lacking. A 66-year-old man presented with two months of right eyelid drooping and vertical diplopia. Examination showed bilateral ophthalmoparesis and complete right ptosis. The remainder of his exam was normal, and an MRI showed small EOMs. Acetylcholine receptor antibodies were elevated, establishing the diagnosis of MG. Oral corticosteroids and pyridostigmine followed by azathioprine improved his ptosis, but not his ophthalmoparesis. One year later he had surgical correction of his diplopia, and the resected superior rectus muscle showed complete replacement of EOM by connective tissue. MG can rarely cause bilateral EOM atrophy, which is characterized histologically by fibrosis in the muscle itself. Atrophy in the EOMs of a myasthenic patient may indicate a poor response to medical management alone.
文摘AIM:To study the electromyogram and muscular pathological features of adult sp inal muscular atrophy(SMA4).METHODS:46 cases of SMA4 were evaluated based on cli nical,histopathology,enzyme histochemistry and ultrastructure.RESULTS:A mean age of the patients with SMA4 was 38.7 years,clinical progressed was slowly.Clinic manifestations mainly appeared proximal muscular weakness and progressive muscul ar atrophy,and there was a relatively good prognosis.Laboratory found:one-fourt h of the disease had elevated serum creatine kinase levels.Eletromyogram reveale d neurogenic damages. The muscular pathological changes showed small groups of a trophy of denervation,ATPase reaction showed fibre-type grouping of renervation and hypertrophy in muscle fibers.CONCLUSION:Muscle biopsy was important;it coul d to help to establish to diagnose the disorder and provided available cases for gene study.
基金supported by the National Natural Science Foundation of China,No.816019591003263(to JXW)the National Basic Research Program of China(973 Program),No.2014CB542203(to LC)
文摘In treating patients with obstetric brachial plexus palsy,we noticed that denervated intrinsic muscles of the hand become irreversibly atrophic at a faster than denervated biceps.In a rat model of obstetric brachial plexus palsy,denervated intrinsic musculature of the forepaw entered the irreversible atrophy far earlier than denervated biceps.In this study,isobaric tags for relative and absolute quantitation were examined in the intrinsic musculature of forepaw and biceps on denervated and normal sides at 3 and 5 weeks to identify dysregulated proteins.Enrichment of pathways mapped by those proteins was analyzed by Kyoto Encyclopedia of Genes and Genomes analysis.At 3 weeks,119 dysregulated proteins in denervated intrinsic musculature of the forepaw were mapped to nine pathways for muscle regulation,while 67 dysregulated proteins were mapped to three such pathways at 5 weeks.At 3 weeks,27 upregulated proteins were mapped to five pathways involving inflammation and apoptosis,while two upregulated proteins were mapped to one such pathway at 5 weeks.At 3 and 5 weeks,53 proteins from pathways involving regrowth and differentiation were downregulated.At 3 weeks,64 dysregulated proteins in denervated biceps were mapped to five pathways involving muscle regulation,while,five dysregulated proteins were mapped to three such pathways at 5 weeks.One protein mapped to inflammation and apoptotic pathways was upregulated from one pathway at 3 weeks,while three proteins were downregulated from two other pathways at 5 weeks.Four proteins mapped to regrowth and differentiation pathways were upregulated from three pathways at 3 weeks,while two proteins were downregulated in another pathway at 5 weeks.These results implicated inflammation and apoptosis as critical factors aggravating atrophy of denervated intrinsic muscles of the hand during obstetric brachial plexus palsy.All experimental procedures and protocols were approved by the Experimental Animal Ethics Committee of Fudan University,China(approval No.DF-325)in January 2015.
基金supported by Basic Science Research Program through the National Research Foundation of Korea (NRF)funded by the Ministry of Education (NRF-2016R1D1A1B01014260)
文摘The purpose of this study was to investigate the intensity-specific regenerative effects of microcurrent therapy on gastrocnemius muscle atrophy induced by cast-immobilization in rabbits. Fifteen rabbits were randomly allocated to 3 groups after cast removal: cast-immobilization and sham microcurrent therapy for 2 weeks(group 1); castimmobilization and microcurrent therapy(25 μA) for 2 weeks(group 2); cast-immobilization and microcurrent therapy(5,000 μA) for 2 weeks(group 3). Clinical parameters [calf circumference, compound muscle action potential(CMAP) of the tibial nerve, thickness of gastrocnemius muscle], cross sectional area of gastrocnemius muscle fibres,and immunohistochemistry was evaluated. The clinical parameters representing mean atrophic changes in group 2 were significantly lower than those in group 3. The cross sectional area of the gastrocnemius muscle fibres and immunohistochemical parameters in group 2 were significantly greater than those in group 3. The results showed that low-intensity microcurrent therapy can more effectively promote regeneration in atrophied gastrocnemius muscle than high-intensity microcurrent therapy.