Mitochondrial dysfunction in type 2 diabetes:A neglected path to skeletal muscle atrophy

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.

Functional recovery and muscle atrophy in pre-clinical models of peripheral nerve transection and gap-grafting in mice:effects of 4-aminopyridine

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.

Pharmacological effects of denervated muscle atrophy due to metabolic imbalance in different periods

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.

Screening and verification of the lncRNA-miRNA-mRNA regulatory network in muscle atrophy after spinal cord injury

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.

The role of 5′-adenosine monophosphate-activated protein kinase(AMPK)in skeletal muscle atrophy

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.

Effects of Neuromuscular Electrical Stimulation in Combination with Glutamine Administration on Skeletal Muscle Atrophy in Colon-26 Tumor-Bearing Mice

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.

GSK3β inhibitor promotes myelination and mitigates muscle atrophy after peripheral nerve injury

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.

Exercise attenuates angiotensinⅡ-induced muscle atrophy by targeting PPARγ/miR-29b

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.

THE ROLE OF MUSCLE SPINDLE IN MUSCLE ATROPHY INDUCED BY SIMULATED MICROGRAVITY

Objective To compare the cross section area (CSA) and the immunoreactivity of conjugated ubiquitin in soleus extrafusal and intrafusal fibers after simulated microgravity and to demonstrate the role of muscle spindle in muscle atrophy induced by simulated microgravity. Methods The immunohistochemical technique (ABC) and image analysis were used to assess the conjugated ubiquitin immunostaining and the cross sectional area of intrafusal and extrafusal fibers of soleus in simulated microgravity rats. Results ①Tail suspension caused a progressive loss of soleus mass. Mean fiber CSA of extrafusal fibers were (7±2)%, (21±4)% and (32±7)% smaller after 3 days, 7 days and 14 days suspension, respectively. While the CAS of intrafusal fibers (bag + chain fibers) were (14±3)% ( P < 0.05 ), (30±7)% ( P < 0.01 ) and (44±10)% ( P < 0.01 ) smaller after 3 days, 7 days and 14 days suspension. ② The immunoreactivity of conjugated ubiquitin both in extrafusal and intrafusal fibers increased after tail suspension. The immunoreactivity of intrafusal fibers increased 1 day after suspension and reached the hightest level at 3 days after tail suspension. The immunoreactivity of extrafusal fibers increased after 3 days suspension and reached the highest level after 7 days tail suspension, which was lower than that in intrafusal fibers after 3 days tail suspension. Conclusion These results suggest that soleus atrophy of intrafusal fibers caused by tail suspension is earlier and more severe than that in extrafusal fibers.

Jianpi Decoction Combined with Medroxyprogesterone Acetate Alleviates Cancer Cachexia and Prevents Muscle Atrophy by Directly Inhibiting E3 Ubiquitin Ligase

ObjectiveTo provide comprehensive evidence for the anti-cancer cachexia effect of Jianpi Decoction(JP)and to explore its mechanism of anti-cancer cachexia.MethodsA mouse model of colon cancer(CT26)-induced cancer cachexia(CC)was used to investigate the anti-CC effect of JP combined with medroxyprogesterone acetate(MPA).Thirty-six mice were equally divided into 6 groups:normal control,CC,MPA(100 mg·kg^(−1)·d^(−1)),MPA+low-dose(20 mg·kg^(−1)·d^(−1))JP(L-JP),MPA+medium-dose(30 mg·kg^(−1)·d^(−1))JP(M-JP),and MPA+high-dose(40 mg·kg^(−1)·d^(−1))JP(H-JP)groups.After successful modeling,the mice were administered by gavage for 11 d.The body weight and tumor volume were measured and recorded every 2 d starting on the 8th day after implantation.The liver,heart,spleen,lung,kidney,tumor and gastrocnemius muscle of mice were collected and weighed.The pathological changes of the tumor was observed,and the cross-sectional area of the gastrocnemius muscle was calculated.The protein expressions of STAT3 and E3 ubiquitinase in the gastrocnemius muscle were measured by Western blot.In addition,an in vitro C2C12 myotube formation model was established to investigate the role of JP in hindering dexamethasone-induced muscle atrophy.In vitro experiments were divided into control,model,and JP serum groups.After 2-d administration,microscopic photographs were taken and myotube diameters were calculated.Western blot was performed to measure the protein expressions of STAT3 and E3 ubiquitinase.ResultsJP combined with MPA restored tumor-induced weight loss(P<0.05,vs.CC)and muscle fiber size(P<0.01,vs.CC).Mechanistically,JP reduced the expression of atrophy-related proteins MuRF1 and MAFbx in tumor-induced muscle atrophy in vivo(P<0.05,vs.CC).In addition,JP reduced the expression of atrophy-related proteins MuRF1 and MAFbx and p-STAT3 phosphorylation(P<0.05 or P<0.01 vs.model group)in C2C12 myotubes treated with dexamethasone in vitro.ConclusionsAdministration of JP combined with MPA restores tumor-induced cachexia conditions.In addition,the profound effect of JP combined with MPA on tumor-induced cachexia may be due to its inhibition of muscle proteolysis(E3 ubiquitinase system).

Pathophysiological changes of muscle after ischemic stroke:a secondary consequence of stroke injury

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.

Inflammation and apoptosis accelerate progression to irreversible atrophy in denervated intrinsic muscles of the hand compared with biceps: proteomic analysis of a rat model of obstetric brachial plexus palsy

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.

Transferrin receptor 1 plays an important role in muscle development and denervation-induced muscular atrophy

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.

Effect of a combination of astaxanthin supplementation, heat stress, and intermittent reloading on satellite cells during disuse muscle atrophy

We examined the effect of a combination of astaxanthin （AX） supplementation, repeated heat stress, and intermittent reloading （IR） on satellite cells in unloaded rat soleus muscles. Forty-nine male Wistar rats （8-week-old） were divided into control, hind-limb unweighting （HU）, IR during HU, IR with AX supplementation, IR with repeated heat stress （41.0-41.5 ℃ for 30 min）, and IR with AX supplementation and repeated heat stress groups. After the experimental period, the antigravitational soleus muscle was analyzed using an immunohistochemical technique. Our results revealed that the combination of dietary AX supplementation and heat stress resulted in protection against disuse muscle atrophy in the soteus muscle. This protective effect may be partially due to a higher satellite cell number in the atrophied soleus muscle in the IR/AX/heat stress group compared with the numbers found in the other groups. We concluded that the combination treatment with dietary AX supplementation and repeated heat stress attenuates soleus muscle atrophy, in part by increasing the number of satellite cells.

Evaluating neuromuscular electrical stimulation for preventing and managing intensive care unit-acquired weakness:Current evidence and future directions

Intensive care unit-acquired weakness(ICU-AW)is a prevalent issue in critical care,leading to significant muscle atrophy and functional impairment.Aiming to address this,Neuromuscular Electrical Stimulation(NMES)has been explored as a therapy.This systematic review assesses NMES's safety and effectiveness in enhancing functional capacity and mobility in pre-and post-cardiac surgery patients.NMES was generally safe and feasible,with intervention sessions varying in frequency and duration.Improvements in muscle strength and 6-minute walking test distances were observed,particularly in preoperative settings,but postoperative benefits were inconsistent.NMES showed promise in preventing muscle loss and improving strength,although its impact on overall functional capacity remained uncertain.Challenges such as short ICU stays and body composition affecting NMES efficacy were noted.NMES also holds potential for other conditions like cerebral palsy and stroke.Further research is needed to optimize NMES protocols and better understand its full benefits in preventing ICU-AW and improving patient outcomes.

GDNF to the rescue:GDNF delivery effects on motor neurons and nerves,and muscle re-innervation after peripheral nerve injuries

Peripheral nerve injuries commonly occur due to trauma,like a traffic accident.Peripheral nerves get severed,causing motor neuron death and potential muscle atrophy.The current golden standard to treat peripheral nerve lesions,especially lesions with large(≥3 cm)nerve gaps,is the use of a nerve autograft or reimplantation in cases where nerve root avulsions occur.If not tended early,degeneration of motor neurons and loss of axon regeneration can occur,leading to loss of function.Although surgical procedures exist,patients often do not fully recover,and quality of life deteriorates.Peripheral nerves have limited regeneration,and it is usually mediated by Schwann cells and neurotrophic factors,like glial cell line-derived neurotrophic factor,as seen in Wallerian degeneration.Glial cell line-derived neurotrophic factor is a neurotrophic factor known to promote motor neuron survival and neurite outgrowth.Glial cell line-derived neurotrophic factor is upregulated in different forms of nerve injuries like axotomy,sciatic nerve crush,and compression,thus creating great interest to explore this protein as a potential treatment for peripheral nerve injuries.Exogenous glial cell line-derived neurotrophic factor has shown positive effects in regeneration and functional recovery when applied in experimental models of peripheral nerve injuries.In this review,we discuss the mechanism of repair provided by Schwann cells and upregulation of glial cell line-derived neurotrophic factor,the latest findings on the effects of glial cell line-derived neurotrophic factor in different types of peripheral nerve injuries,delivery systems,and complementary treatments(electrical muscle stimulation and exercise).Understanding and overcoming the challenges of proper timing and glial cell line-derived neurotrophic factor delivery is paramount to creating novel treatments to tend to peripheral nerve injuries to improve patients'quality of life.

Direct muscle neurotization after end-to-end and end-to-side neurorrhaphy An experimental study in the rat forelimb model

The need for the continuous research of new tools for improving motor function recovery after nerve injury is justified by the still often unsatisfactory clinical outcome in these patients. It has been previously shown that the combined use of two reconstructive techniques, namely end-to-side neurorrhaphy and direct muscle neurotization in the rat hindlimb model, can lead to good results in terms of skeletal muscle reinnervation. Here we show that, in the rat forelimb model, the combined use of direct muscle neurotization with either end-to-end or end-to-side neurorrhaphy to reinnervate the denervated flexor digitorum muscles, leads to muscle atrophy prevention over a long postoperative time lapse （10 months）. By contrast, very little motor recovery （in case of end-to-end neurorrhaphy） and almost no motor recovery （in case of end-to-side neurorrhaphy） were observed in the grasping activity controlled by flexor digitorum muscles. It can thus be concluded that, at least in the rat, direct muscle neurotization after both end-to-end and end-to-side neurorrhaphy represents a good strategy for preventing denervation-related muscle atrophy but not for regaining the lost motor function.

Skeletal muscle cell apoptosis following motor nerve injury versus sensory nerve injury

Skeletal muscle atrophy inevitably occurs in denervated skeletal muscle, and cell apoptosis plays an important role in skeletal muscle atrophy and degeneration. The present study established rat models of simple nerve injury by transecting the ventral or dorsal spinal nerve root and observed rat skeletal muscle cell apoptosis following simple motor nerve injury versus simple sensory nerve injury. Following skeletal muscle denervation for 10 weeks, cell apoptosis was detected in skeletal muscle, which was accompanied by obvious changes in rat behavior and electrophysiological responses. In addition, changes in cross-sectional area and average gray-scale of motor endplates of the gastrocnemius muscle were analyzed following sciatic nerve injury and motor nerve injury. Cell nuclei in denervated skeletal muscle tissue were more densely arranged than in normal skeletal muscle tissue. Cell nuclei were most dense in the sciatic nerve injury group, followed by the motor nerve injury group and the sensory nerve injury group. Fas/FasL expression and the number of apoptotic cells increased in denervated skeletal muscle, and apoptosis-related changes were observed. These findings suggested that motor and sensory nerves provided trophic actions following skeletal muscle and motor nerve injury, resulting in a greater influence on skeletal muscle atrophy than sensory nerve injury. Therefore, reconstruction of motor nerves should be preferentially considered for treating denervation-induced skeletal muscle atrophy.

Considerations on the concept, definition, and diagnosis of amyotrophic lateral sclerosis

The concept, definition, and diagnosis of amyotrophic lateral sclerosis(ALS) currently present some problems. This article systematically reviews the literature on the history, current concepts, definition, and diagnosis of ALS, and discloses the present problems based on the retrieved literature and the authors' clinical experience. The current concepts and definitions of ALS have not yet been unified or standardized in clinical practice, and are sometimes vague or inaccurate, which can cause difficulties for neurologists in the clinical treatment of ALS. The concept and definition of ALS need to be further ascertained, and the current diagnostic criteria for ALS require further development. The identification of effective and objective biomarkers may be a feasible method for the early and accurate diagnosis of ALS. Therefore, future research should focus on the identification of reliable biomarkers—especially neuroimaging biomarkers—through autopsy. Standardizing the concept and definition of ALS and formulating clear diagnostic criteria will largely avoid many uncertainties in the future clinical research and treatment of ALS, which will greatly benefit patients.

Exosome-mediated regulatory mechanisms in skeletal muscle:a narrative review

Skeletal muscle plays a paramount role in physical activity,metabolism,and energy balance,while its homeostasis is being challenged by multiple unfavorable factors such as injury,aging,or obesity.Exosomes,a subset of extracellular vesicles,are now recognized as essential mediators of intercellular communication,holding great clinical potential in the treatment of skeletal muscle diseases.Herein,we outline the recent research progress in exosomal isolation,characterization,and mechanism of action,and emphatically discuss current advances in exosomes derived from multiple organs and tissues,and engineered exosomes regarding the regulation of physiological and pathological development of skeletal muscle.These remarkable advances expand our understanding of myogenesis and muscle diseases.Meanwhile,the engineered exosome,as an endogenous nanocarrier combined with advanced design methodologies of biomolecules,will help to open up innovative therapeutic perspectives for the treatment of muscle diseases.