miRNA targeted signaling pathway in the early stage of denervated fast and slow muscle atrophy

Denervation often results in skeletal muscle atrophy.Different mechanisms seem to be involved in the determination between denervated slow and fast skeletal muscle atrophy.At the epigenetic level,mi RNAs are thought to be highly involved in the pathophysiological progress of denervated muscles.We used mi RNA microarrays to determine mi RNA expression profiles from a typical slow muscle（soleus muscle） and a typical fast muscle（tibialis anterior muscle） at an early denervation stage in a rat model.Results showed that mi R-206,mi R-195,mi R-23 a,and mi R-30 e might be key factors in the transformation process from slow to fast muscle in denervated slow muscles.Additionally,certain mi RNA molecules（mi R-214,mi R-221,mi R-222,mi R-152,mi R-320,and Let-7e） could be key regulatory factors in the denervated atrophy process involved in fast muscle.Analysis of signaling pathway networks revealed the mi RNA molecules that were responsible for regulating certain signaling pathways,which were the final targets（e.g.,p38 MAPK pathway; Pax3/Pax7 regulates Utrophin and follistatin by HDAC4; IGF1/PI3K/Akt/m TOR pathway regulates atrogin-1 and Mu RF1 expression via Fox O phosphorylation）.Our results provide a better understanding of the mechanisms of denervated skeletal muscle pathophysiology.

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.

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.

Short-term observations of the regenerative potential of injured proximal sensory nerves crossed with distal motor nerves

Motor nerves and sensory nerves conduct signals in different directions and function in different ways.In the surgical treatment of peripheral nerve injuries,the best prognosis is obtained by keeping the motor and sensory nerves separated and repairing the nerves using the suture method.However,the clinical consequences of connections between sensory and motor nerves currently remain unknown.In this study,we analyzed the anatomical structure of the rat femoral nerve,and observed the motor and sensory branches of the femoral nerve in the quadriceps femoris.After ligation of the nerves,the proximal end of the sensory nerve was connected with the distal end of the motor nerve,followed by observation of the changes in the newly-formed regenerated nerve fibers.Acetylcholinesterase staining was used to distinguish between the myelinated and unmyelinated motor and sensory nerves.Denervated muscle and newly formed nerves were compared in terms of morphology,electrophysiology and histochemistry.At 8 weeks after connection,no motor nerve fibers were observed on either side of the nerve conduit and the number of nerve fibers increased at the proximal end.The proportion of newly-formed motor and sensory fibers was different on both sides of the conduit.The area occupied by autonomic nerves in the proximal regenerative nerve was limited,but no distinct myelin sheath was visible in the distal nerve.These results confirm that sensory and motor nerves cannot be effectively connected.Moreover,the change of target organ at the distal end affects the type of nerves at the proximal end.

Stimulating effect of thyroid hormones in peripheral nerve regeneration:research history and future direction toward clinical therapy

Injury to peripheral nerves is often observed in the clinic and severe injuries may cause loss of motor and sensory functions.Despite extensive investigation,testing various surgical repair techniques and neurotrophic molecules,at present,a satisfactory method to ensuring successful recovery does not exist.For successful molecular therapy in nerve regeneration,it is essential to improve the intrinsic ability of neurons to survive and to increase the speed of axonal outgrowth.Also to induce Schwann cell phenotypical changes to prepare the local environment favorable for axonal regeneration and myelination.Therefore,any molecule that regulates gene expression of both neurons and Schwann cells could play a crucial role in peripheral nerve regeneration.Clinical and experimental studies have reported that thyroid hormones are essential for the normal development and function of the nervous system,so they could be candidates for nervous system regeneration.This review provides an overview of studies devoted to testing the effect of thyroid hormones on peripheral nerve regeneration.Also it emphasizes the importance of combining biodegradable tubes with local administration of triiodothyronine for future clinical therapy of human severe injured nerves.We highlight that the local and single administration of triiodothyronine within biodegradable nerve guide improves significantly the regeneration of severed peripheral nerves,and accelerates functional recovering.This technique provides a serious step towards future clinical application of triiodothyronine in human severe injured nerves.The possible regulatory mechanism by which triiodothyronine stimulates peripheral nerve regeneration is a rapid action on both axotomized neurons and Schwann cells.

The observation of transplanted embryonic motoneurons in the denervated muscles of adult rats

OBJECTIVE: To observe the survival of embryonic motoneurons after they were transplanted into the denervated skeletal muscles and to find a new method to retard the atrophy of denervated muscles. METHODS: Dissociated embryonic motoneurons prelabled with 5-bromo-2'-deoxyuridine (Brdur) on the embryonic days 12 were injected into the denervated gastrocnemius muscles of adult rats. Then gastrocnemius muscles were processed with Nissl staining, acetylcholinesterase staining and Brdur immunocytochemical staining to show the implanted motoneurons at 9 and 22 weeks post-transplantation. Myofibrillar ATPase staining was used to show the morphology of muscle fibers. The rats in experimental group were implanted with embryonic motoneurons in the predenervation muscles, while the rats in control group were injected with just culture medium without motoneurons. RESULTS: Embryonic motoneurons survived, developed and extended long axons to form neuromuscular junctions with the denervated muscles. The differentiation of muscle fibers and fiber type grouping occurred among bigger fibers in experimental group. The transverse area was smaller and there was no apparent fiber type grouping in control group. CONCLUSIONS: Embryonic motoneurons can survive, develop and reinnervate denervated muscles after being transplanted into denervated muscles. It is worth further investigating on ameliorating the atrophy of denervated muscle.