The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.

Skeletal muscle is the largest metabolic organ of the human body. Maintaining the best quality control and functional integrity of mitochondria is essential for the health of skeletal muscle. However, mitochondrial dysfunction characterized by mitochondrial dynamic imbalance and mitophagy disruption can lead to varying degrees of muscle atrophy, but the underlying mechanism of action is still unclear. Although mitochondrial dynamics and mitophagy are two different mitochondrial quality control mechanisms, a large amount of evidence has indicated that they are interrelated and mutually regulated. The former maintains the balance of the mitochondrial network, eliminates damaged or aged mitochondria, and enables cells to survive normally. The latter degrades damaged or aged mitochondria through the lysosomal pathway, ensuring cellular functional health and metabolic homeostasis. Skeletal muscle atrophy is considered an urgent global health issue. Understanding and gaining knowledge about muscle atrophy caused by mitochondrial dysfunction, particularly focusing on mitochondrial dynamics and mitochondrial autophagy, can greatly contribute to the prevention and treatment of muscle atrophy. In this review, we critically summarize the recent research progress on mitochondrial dynamics and mitophagy in skeletal muscle atrophy, and expound on the intrinsic molecular mechanism of skeletal muscle atrophy caused by mitochondrial dynamics and mitophagy. Importantly, we emphasize the potential of targeting mitochondrial dynamics and mitophagy as therapeutic strategies for the prevention and treatment of muscle atrophy, including pharmacological treatment and exercise therapy, and summarize effective methods for the treatment of skeletal muscle atrophy.

MicroRNA­mediated regulation of muscular atrophy: Exploring molecular pathways and therapeutics (Review).

Muscular atrophy, which results in loss of muscle mass and strength, is a significant concern for patients with various diseases. It is crucial to comprehend the molecular mechanisms underlying this condition to devise targeted treatments. MicroRNAs (miRNAs) have emerged as key regulators of gene expression, serving vital roles in numerous cellular processes, including the maintenance of muscle stability. An intricate network of miRNAs finely regulates gene expression, influencing pathways related to muscle protein production, and muscle breakdown and regeneration. Dysregulation of specific miRNAs has been linked to the development of muscular atrophy, affecting important signaling pathways including the protein kinase B/mTOR and ubiquitin­proteasome systems. The present review summarizes recent work on miRNA patterns associated with muscular atrophy under various physiological and pathological conditions, elucidating its intricate regulatory networks. In conclusion, the present review lays a foundation for the development of novel treatment options for individuals affected by muscular atrophy, and explores other regulatory pathways, such as autophagy and inflammatory signaling, to ensure a comprehensive overview of the multifarious nature of muscular atrophy. The objective of the present review was to elucidate the complex molecular pathways involved in muscular atrophy, and to facilitate the development of innovative and specific therapeutic strategies for the prevention or reversal of muscular atrophy in diverse clinical scenarios.

Satellite Cell-Derived Exosomes: A Novel Approach to Alleviate Skeletal Muscle Atrophy and Fibrosis.

Skeletal muscle atrophy coincides with extensive fibrous tissue hyperplasia in muscle-atrophied patients, and fibrous tissue plays a vital role in skeletal muscle function and hinders muscle fiber regeneration. However, effective drugs to manage skeletal muscle atrophy and fibrosis remain elusive. This study isolated and characterized exosomes derived from skeletal muscle satellite cells (MuSC-Exo). The study investigated their effects on denervated skeletal muscle atrophy and fibrosis in Sprague Dawley (SD) rats via intramuscular injection. MuSC-Exo demonstrated the potential to alleviate skeletal muscle atrophy and fibrosis. The underlying mechanism using single-cell RNA sequencing data and functional analysis are analyzed. Mechanistic studies reveal close associations between fibroblasts and myoblasts, with the transforming growth factor ß1 (TGF-ß1)-Smad3-Pax7 axis governing fibroblast activation in atrophic skeletal muscle. MuSC-Exo intervention inhibited the TGF-ß1/Smad3 pathway and improved muscle atrophy and fibrosis. In conclusion, MuSC-Exo-based therapy may represent a novel strategy to alleviate skeletal muscle atrophy and reduce excessive fibrotic tissue by targeting Pax7 through the TGF-ß1/Smad3 pathway.

Electroacupuncture Promotes Skeletal Muscle Myogenic Differentiation and Protein Synthesis by Reducing Let-7c-5p Levels.

Objective: Acupuncture with low-frequency electrical stimulation (Acu-LFES) can attenuate muscle atrophy. Previous studies have found that Acu-LFES reduces the let-7 family in serum exosomes. This study explored the effects of let-7c-5p in chronic kidney disease (CKD) muscle atrophy. Methods: A total of 24 mice were randomly divided into control group, Acu-LFES group, CKD group, and CKD/Acu-LFES group (n = 6/group). The 5/6 nephrectomy was performed to establish the CKD model in mice. After 20 weeks, the Acu-LFES group and CKD/Acu-LFES group were treated with electroacupuncture at the "Zu San Li" and "Yang Ling Quan" bilaterally points for 15 minutes once. Surface sensing of translation (SUnSET), Reverse Transcription-quantitative PCR(RT-qPCR), immunofluorescence staining, and Western blot were performed to examine each group's state of protein production and myogenic differentiation. we knocked down or exogenously expressed let-7c-5p in C2C12 myoblast, RT-qPCR, and Western blot were performed to examine protein synthesis and myogenic differentiation. Results: The protein expressions of MyoD and Myogenin (MyoG) were decreased in the CKD group (P = .029 and P = .026) concomitant with a decrease in the muscle fiber cross-sectional area. Acu-LFES prevented muscle atrophy in CKD mice. The protein expressions of MyoD and MyoG were increased in the CKD/Acu-LFES group (P = .006 and P = .001). In muscle of CKD mice, IGF1, IGF1R, IRS1, phosphorylated mTOR and P70S6K proteins were decreased compared with control muscle (P = .001, P = .007, P < .001, P < .001 and P < .001), whereas atrogin-1/MAFbx and MuRF1 were dramatically increased (P < .001). Acu-LFES reversed these phenomena, indicating IGF1/mTOR signaling pathway was induced to promote muscle protein synthesis and myogenic differentiation. Meanwhile, Acu-LFES caused a decrease of let-7c-5p in skeletal muscle of CKD mice (P = .034). Inhibiting let-7c-5p promoted C2C12 myogenic differentiation (P = .002 and P = .001) and increased IGF1, IGF1R, IRS1 levels while upregulating mTOR and P70S6K phosphorylation (P < .001, P = .002, P = .009, P < .001 and P = .007). It is interesting to observe that the abundance of atrogin-1/MAFbx and MuRF-1 was unaffected by let-7c-5p (P > .05). Conclusions: Acu-LFES-reduced expression of let-7c-5p can ameliorate CKD-induced skeletal muscle atrophy by upregulating the IGF1/mTOR signaling pathway, which enhances skeletal muscle protein synthesis and myogenic differentiation. Let-7c-5p may be a potential regulator for the treatment of muscle atrophy.

Effects of exercise, metformin, and combination treatments on type 2 diabetic mellitus-induced muscle atrophy in db/db mice: Crosstalk between autophagy and the proteasome.

Both exercise and metformin are common effective clinical treatments of type 2 diabetic mellitus. This study investigated the functional role of exercise, metformin, and combination treatment on type 2 diabetic mellitus-induced muscle atrophy. In this experiment, a total of 10 BKS mice were set as the control group. A total of 40 BKS-db/db mice were randomly divided into the control group (db/db); the exercise intervention group (db/db + Ex), which ran on a treadmill at 7-12 m/min, 30-40 min/day, 5 days/week; the metformin administration group (db/db + Met), which was administered 300 mg/kg of metformin solution by gavage daily; and the exercise combined with metformin administration group (db/db + Ex + Met). After 8 weeks of intervention, their tibialis anterior muscles were removed. The levels of insulin signaling pathway proteins, ubiquitin proteasome, and autophagic lysosome-associated proteins were detected using western blot, the expression of MuRF1 and Atrogin-1 was detected using immunohistochemical staining, and the degradation of autophagosomes was detected using double-labeled immunofluorescence. The db/db mice exhibited reduced insulin sensitivity and inhibition of the autophagic-lysosome system, the ubiquitin-proteasome system was activated, and protein degradation was exacerbated, leading to skeletal muscle atrophy. Exercise and metformin and their combined interventions can increase insulin sensitivity, whereas exercise alone showed more effective in inhibiting the ubiquitin-proteasome system, improving autophagy levels, and alleviating skeletal muscle atrophy. Compared with metformin, exercise demonstrated superior improvement of muscle atrophy by promoting the synthesis and degradation of autophagy through the AMPK/ULK1 pathway. However, the combination treatment exhibits no synergistic effect on muscle atrophy.

Effect of ST36 electroacupuncture on the switch of skeletal muscle fibres in mice with sciatic nerve dissociation.

Skeletal muscle is striated muscle that moves autonomously and is innervated by peripheral nerves. Peripheral nerve injury is very common in clinical treatment. However, the commonly used treatment methods often focus on the regeneration of the injured nerve but overlook the pathological changes in the injured skeletal muscle. Acupuncture, as the main treatment for denervated skeletal muscle atrophy, is used extensively in clinical practice. In the present study, a mouse model of lower limb sciatic nerve detachment was constructed and treated with electroacupuncture Stomach 36 to observe the atrophy of lower limb skeletal muscle and changes in skeletal muscle fibre types before and after electroacupuncture Stomach 36 treatment. Mice with skeletal muscle denervation showed a decrease in the proportion of IIa muscle fibres and an increase in the proportion of IIb muscle fibres, after electroacupuncture Stomach 36. The changes were reversed by specific activators of p38 MAPK, which increased IIa myofibre ratio. The results suggest that electroacupuncture Stomach 36 can reverse the change of muscle fibre type from IIb to IIa after denervation of skeletal muscle by inhibiting p38 MAPK. The results provide an important theoretical basis for the treatment of clinical peripheral nerve injury diseases with electroacupuncture, in addition to novel insights that could facilitate the study of pathological changes of denervated skeletal muscle.

Effects of electroacupuncture at "Jiaji" (EX-B 2) combined with neurodynamic mobilization on gastrocnemius muscle atrophy and expression of NF-κB and MuRF1 in rabbits after sciatic nerve injury. / 电针"夹脊"ç»“åˆç¥žç»æ¾åŠ¨æœ¯å¯¹åéª¨ç¥žç»æŸä¼¤å ”è “è‚ è‚ŒèŽç¼©åŠNF-κB、MuRF1表达的影响.

OBJECTIVES: To observe the effects of electroacupuncture (EA) at "Jiaji" (EX-B 2) combined with neurodynamic mobilization (NM) on the cross-sectional area of the gastrocnemius muscle fibers after sciatic nerve injury in rabbits, and the expression of nuclear factor κB (NF-κB) and muscle-specific ring-finger protein 1 (MuRF1). METHODS: A total of 180 common-grade New Zealand rabbits (half male and half female) were randomly divided into five groups, i.e. a normal control group, a model control group, a NM group, an EA group and a combined intervention group, 36 rabbits in each group. Except in the normal control group, clipping method was used to prepare the model of sciatic nerve injury in the rest groups. On the 3rd day of successful modeling, NM was delivered in the NM group. In the EA group, EA was exerted at bilateral "Jiaji" (EX-B 2) of L4 to L6, stimulated with disperse-dense wave and the frequency of 2 Hz/100 Hz. In the combined intervention group, after EA delivered at bilateral "Jiaji" (EX-B 2) of L4 to L6 , NM was operated. The intervention in each group was delivered once daily, for 6 days a week, and lasted 1, 2 or 4 weeks according to the collection time of sample tissue. After 1, 2 and 4 weeks of intervention, in each group, the toe tension reflex score and the modified Tarlov test score were observed; the morphology of the gastrocnemius muscle was observed by HE staining and the cross-sectional area of muscular fiber was measured; using Western blot method, the expression of NF-κB and MuRF1 of the gastrocnemius muscle was detected. RESULTS: After 1, 2 and 4 weeks of intervention, the toe tension reflex scores and the modified Tarlov scores in the model control group were lower than those of the normal control group (P<0.05), and these two scores in the NM group, the EA group and the combined intervention group were all higher than those of the model control group (P<0.05); the scores in the combined intervention group were higher than those in the EA group and the NM group (P<0.05). The gastrocnemius fibers were well arranged and the myocyte morphology was normal in the normal control group. In the model control group, the gastrocnemius fibers were disarranged, the myocytes were irregular in morphology and the inflammatory cells were infiltrated in the local. In the NM group, the EA group and the combined intervention group, the muscle fibers were regularly arranged when compared with the model control group. After 1, 2 and 4 weeks of intervention, the cross-sectional areas of the gastrocnemius muscle fibers in the model control group were smaller than those of the normal control group (P<0.05). The cross-sectional areas in the NM group, the EA group and the combined intervention group were larger than those of the model control group (P<0.05), and the cross-sectional areas in the combined intervention group were larger than those in the NM group and the EA group (P<0.05). After intervention for 1, 2 and 4 weeks, the protein expressions of NF-κB and MuRF1 in the gastrocnemius muscle were higher in the model control group in comparison of those in the normal control group (P<0.05). In the NM group, the EA group and the combined intervention group, the expressions of NF-κB after intervention for 1, 2 and 4 weeks and the expressions of MuRF1 after 2 and 4 weeks of intervention were lower when compared with those in the model control group (P<0.05). In the combined intervention group, the protein expressions of NF-κB after intervention for 1, 2 and 4 weeks and the expressions of MuRF1 after 2 and 4 weeks of intervention were decreased when compared with those in the NM group and the EA group (P<0.05). CONCLUSIONS: Electroacupuncture at "Jiaji" (EX-B 2) combined with NM may increase the muscle strength and sciatic function and alleviate gastrocnemius muscle atrophy in the rabbits with sciatic nerve injury. The underlying mechanism is related to the inhibition of NF-κB and MuRF1 expression.

Electrical stimulation mitigates muscle degradation shift in gene expressions during 12-h mechanical ventilation.

Ventilator-induced diaphragm dysfunction (VIDD), a dysfunction of the diaphragm muscle caused by prolonged mechanical ventilation (MV), is an important factor that hinders successful weaning from ventilation. We evaluated the effects of electrical stimulation of the diaphragm muscle (pulsed current with off-time intervals) on genetic changes during 12 h of MV (E-V12). Rats were divided into four groups: control, 12-h MV, sham operation, and E-V12 groups. Transcriptome analysis using an RNA microarray revealed that 12-h MV caused upregulation of genes promoting muscle atrophy and downregulation of genes facilitating muscle synthesis, suggesting that 12-h MV is a reasonable method for establishing a VIDD rat model. Of the genes upregulated by 12-h MV, 18 genes were not affected by the sham operation but were downregulated by E-V12. These included genes related to catabolic processes, inflammatory cytokines, and skeletal muscle homeostasis. Of the genes downregulated by 12-h MV, 6 genes were not affected by the sham operation but were upregulated by E-V12. These included genes related to oxygen transport and mitochondrial respiration. These results suggested that 12-h MV shifted gene expression in the diaphragm muscle toward muscle degradation and that electrical stimulation counteracted this shift by suppressing catabolic processes and increasing mitochondrial respiration.

Acute effect of electrical stimulation on muscle protein synthesis and break-down in the soleus muscle of hindlimb unloaded rats.

Electrical stimulation (ES) is effective for disuse-induced muscle atrophy. However, the acute effect of ES on muscle protein synthesis (MPS) and muscle protein breakdown (MPB) remains unclear. We investigated the effect of a single-session ES treatment on mTORC1 signaling, MPS, and MPB in the soleus muscle of 2-week hindlimb unloaded rats. Sprague Dawley rats (n = 12 male) were randomly divided into control (CON) and hindlimb unloaded (HU) groups. After 2 weeks, the right soleus muscle was percutaneously stimulated and underwent supramaximal isometric contractions. The left soleus muscle served as an internal control. We collected soleus muscle samples 6 h after ES. Two weeks of HU decreased p70S6K and S6rp activation, downstream factors for mTORC1 signaling, and SUnSET method-assessed MPS, but increased the LC3-II/I ratio, an indicator of autophagy. ES on disused muscle successfully activated mTORC1 signaling but did not affect MPS. Contrary, ES decreased ubiquitinated proteins expression and LC3B-II/I ratio. HU might affect mTORC1 activation and MPS differently in response to acute ES possibly due to excessive ROS production caused by ES. Our findings suggest that ES applied to disused skeletal muscles may suppress MPB, but its effect on MPS appears to be attenuated.

Weight bearing training alleviates muscle atrophy and pyroptosis of middle-aged rats.

Background: Age-related muscle atrophy and adipose accumulation begin to occur in young and middle-aged individuals, and exercise at an early age improves body composition. Pyroptosis may play an essential role in age-related low-grade inflammation. This study aimed to explore the alleviation of muscle atrophy by weight-bearing training with increasing age via inhibition of pyroptosis. Methods: Ninety 8-month-old male SD rats were randomly divided into three groups: (1) normal baseline group (N group, n = 10), sacrificed after adaptive feeding; control group (C group, n = 40); and weight-bearing running group (R group, n = 40). Blood samples, adipose tissue (AT), and extensor digitorum longus (EDL) were collected after 8, 16, 24, and 32-weeks intervention. Results: The body weight, muscle mass, fat mass, plasma lipid, AT wet weight, adipocyte cross-sectional area (CSA), and apoptosis rates of AT and EDL were increased, while the muscle mass, wet weight, and fiber CSA of EDL were decreased by aging, which were reversed by exercise. Weight-bearing training promoted protein synthesis in EDL, inhibited protein degradation in EDL, and expression of pyroptotic key proteins in EDL and AT in rats. Conclusion: Weight-bearing training improves body composition and alleviates age-related muscle atrophy in rats, and its mechanism may be related to the inhibition of pyroptosis in the EDL and AT and the improvement of muscle protein metabolism.

Polydeoxyribonucleotide and Shock Wave Therapy Sequence Efficacy in Regenerating Immobilized Rabbit Calf Muscles.

This study primarily aimed to investigate the combined effects of polydeoxyribonucleotide (PDRN) and extracorporeal shock wave therapy (ESWT) sequences on the regenerative processes in atrophied animal muscles. Thirty male New Zealand rabbits, aged 12 weeks, were divided into five groups: normal saline (Group 1), PDRN (Group 2), ESWT (Group 3), PDRN injection before ESWT (Group 4), and PDRN injection after ESWT (Group 5). After 2 weeks of cast immobilization, the respective treatments were administered to the atrophied calf muscles. Radial ESWT was performed twice weekly. Calf circumference, tibial nerve compound muscle action potential (CMAP), and gastrocnemius (GCM) muscle thickness after 2 weeks of treatment were evaluated. Histological and immunohistochemical staining, as well as Western blot analysis, were conducted 2 weeks post-treatment. Staining intensity and extent were assessed using semi-quantitative scores. Groups 4 and 5 demonstrated significantly greater calf muscle circumference, GCM muscle thickness, tibial nerve CMAP, and GCM muscle fiber cross-sectional area (type I, type II, and total) than the remaining three groups (p < 0.05), while they did not differ significantly in these parameters. Groups 2 and 3 showed higher values for all the mentioned parameters than Group 1 (p < 0.05). Group 4 had the greatest ratio of vascular endothelial growth factor (VEGF) to platelet endothelial cell adhesion molecule-1 (PECAM-1) in the GCM muscle fibers compared to the other four groups (p < 0.05). Western blot analysis revealed significantly higher expression of angiogenesis cytokines in Groups 4 and 5 than in the other groups (p < 0.05). The combination of ESWT and PDRN injection demonstrated superior regenerative efficacy for atrophied calf muscle tissue in rabbit models compared to these techniques alone or saline. In particular, administering ESWT after PDRN injection yielded the most favorable outcomes in specific parameters.

Extracellular Vesicles for Muscle Atrophy Treatment.

Skeletal muscle atrophy is a progressive chronic disease associated with various conditions, such as aging, cancer, and muscular dystrophy. Interleukin-6 (IL-6) is highly correlated with or plays a crucial role in inducing skeletal muscle atrophy. Extracellular vehicles (EVs), including exosomes, mediate cell-cell communication, and alterations in the genetic material contained in EVs during muscle atrophy may impair muscle cell signaling. Transplantation of muscle progenitor cell-derived EVs (MPC-EVs) is a promising approach for treating muscle diseases such as Duchenne muscular dystrophy (DMD). Moreover, stem cell-derived EVs with modification of microRNAs (e.g., miR-26 and miR-29) have been reported to attenuate muscle atrophy. Unbiased RNA-Seq analysis suggests that MPC-EVs may exert an inhibitory effect on IL-6 pathway. Here, we review the latest advances concerning the mechanisms of stem cell/progenitor cell-derived EVs in alleviating muscle atrophy, including anti-inflammatory and anti-fibrotic effects. We also discuss the clinical application of EVs in the treatment of muscle atrophy.

Mesenchymal stem cells alleviate dexamethasone-induced muscle atrophy in mice and the involvement of ERK1/2 signalling pathway.

BACKGROUND: High dosage of dexamethasone (Dex) is an effective treatment for multiple diseases; however, it is often associated with severe side effects including muscle atrophy, resulting in higher risk of falls and poorer life quality of patients. Cell therapy with mesenchymal stem cells (MSCs) holds promise for regenerative medicine. In this study, we aimed to investigate the therapeutic efficacy of systemic administration of adipose-derived mesenchymal stem cells (ADSCs) in mitigating the loss of muscle mass and strength in mouse model of DEX-induced muscle atrophy. METHODS: 3-month-old female C57BL/6 mice were treated with Dex (20 mg/kg body weight, i.p.) for 10 days to induce muscle atrophy, then subjected to intravenous injection of a single dose of ADSCs ([Formula: see text] cells/kg body weight) or vehicle control. The mice were killed 7 days after ADSCs treatment. Body compositions were measured by animal DXA, gastrocnemius muscle was isolated for ex vivo muscle functional test, histological assessment and Western blot, while tibialis anterior muscles were isolated for RNA-sequencing and qPCR. For in vitro study, C2C12 myoblast cells were cultured under myogenic differentiation medium for 5 days following 100 [Formula: see text]M Dex treatment with or without ADSC-conditioned medium for another 4 days. Samples were collected for qPCR analysis and Western blot analysis. Myotube morphology was measured by myosin heavy chain immunofluorescence staining. RESULTS: ADSC treatment significantly increased body lean mass (10-20%), muscle wet weight (15-30%) and cross-sectional area (CSA) (~ 33%) in DEX-induced muscle atrophy mice model and down-regulated muscle atrophy-associated genes expression (45-65%). Hindlimb grip strength (~ 37%) and forelimb ex vivo muscle contraction property were significantly improved (~ 57%) in the treatment group. Significant increase in type I fibres (~ 77%) was found after ADSC injection. RNA-sequencing results suggested that ERK1/2 signalling pathway might be playing important role underlying the beneficial effect of ADSC treatment, which was confirmed by ERK1/2 inhibitor both in vitro and in vivo. CONCLUSIONS: ADSCs restore the pathogenesis of Dex-induced muscle atrophy with an increased number of type I fibres, stronger muscle strength, faster recovery rate and more anti-fatigue ability via ERK1/2 signalling pathway. The inhibition of muscle atrophy-associated genes by ADSCs offered this treatment as an intervention option for muscle-associated diseases. Taken together, our findings suggested that adipose-derived mesenchymal stem cell therapy could be a new treatment option for patient with Dex-induced muscle atrophy.

Deliberation on debilitating condition of cancer cachexia: Skeletal muscle wasting.

BACKGROUND: Cancer cachexia is a debilitating syndrome associated with marked body loss because of muscular atrophy and fat loss. There are several mechanisms contributing to the pathogenesis of cachexia. The presence of the tumor releases cytokines from inflammatory and immune cells, which play a significant role in activating and deactivating certain pathways associated with protein, carbohydrate, and lipid metabolism. This review focuses on various cascades involving an imbalance between protein synthesis and degradation in the skeletal muscles. OBJECTIVES: This study aimed to elucidate the mechanisms involved in skeletal muscle wasting phenomenon over the last few years. METHODS: This article briefly overviews different pathways responsible for muscle atrophy in cancer cachexia. Studies published up to April 2023 were included. Important findings and study contributions were chosen and compiled using several databases including PubMed, Google Scholar, Science Direct, and ClinicalTrials.gov using relevant keywords. RESULTS: Cancer cachexia is a complex disease involving multiple factors resulting in atrophy of skeletal muscles. Systemic inflammation, altered energy balance and carbohydrate metabolism, altered lipid and protein metabolism, and adipose tissue browning are some of the major culprits in cancer cachexia. Increased protein degradation and decreased protein synthesis lead to muscle atrophy. Changes in signaling pathway like ubiquitin-proteasome, autophagy, mTOR, AMPK, and IGF-1 also lead to muscle wasting. Physical exercise, nutritional supplementation, steroids, myostatin inhibitors, and interventions targeting on inflammation have been investigated to treat cancer cachexia. Some therapy showed positive results in preclinical and clinical settings, although more research on the efficacy and safety of the treatment should be done. CONCLUSION: Muscle atrophy in cancer cachexia is the result of multiple complex mechanisms; as a result, a lot more research has been done to describe the pathophysiology of the disease. Targeted therapy and multimodal interventions can improve clinical outcomes for patients.

Impacts of whole-body vibration on denervated skeletal-muscle atrophy in rats.

Whole-body vibration has been considered as a countermeasure against muscle atrophy. However, its effects on muscle atrophy are poorly understood. We evaluated the effects of whole-body vibration on denervated skeletal muscle atrophy. Whole-body vibration was performed on rats from Day 15 to 28 after denervation injury. Motor performance was evaluated using an inclined-plane test. Compound muscle action potentials of the tibial nerve were examined. Muscle wet weight and muscle fiber cross-sectional area were measured. Myosin heavy chain isoforms were analyzed in both muscle homogenates and single myofibers. Whole-body vibration resulted in a significantly decreased inclination angle and muscle weight, but not muscle fiber cross-sectional area of fast-twitch gastrocnemius compared to denervation only. In denervated gastrocnemius, a fast-to-slow shift was observed in myosin heavy chain isoform composition following whole-body vibration. There were no significant changes in muscle weight, muscle fiber cross-sectional area, and myosin heavy chain isoform composition in denervated slow-twitch soleus. These results imply that whole-body vibration does not promote recovery of denervation-induced muscle atrophy.

Skeletal muscle atrophy, regeneration, and dysfunction in heart failure: Impact of exercise training.

This review highlights some established and some more contemporary mechanisms responsible for heart failure (HF)-induced skeletal muscle wasting and weakness. We first describe the effects of HF on the relationship between protein synthesis and degradation rates, which determine muscle mass, the involvement of the satellite cells for continual muscle regeneration, and changes in myofiber calcium homeostasis linked to contractile dysfunction. We then highlight key mechanistic effects of both aerobic and resistance exercise training on skeletal muscle in HF and outline its application as a beneficial treatment. Overall, HF causes multiple impairments related to autophagy, anabolic-catabolic signaling, satellite cell proliferation, and calcium homeostasis, which together promote fiber atrophy, contractile dysfunction, and impaired regeneration. Although both wasting and weakness are partly rescued by aerobic and resistance exercise training in HF, the effects of satellite cell dynamics remain poorly explored.

Low-intensity pulsed ultrasound and parathyroid hormone improve muscle atrophy in estrogen deficiency mice.

Due to aging and long-term estrogen deficiency, postmenopausal women suffer muscle atrophy (MA), which is characterized by decreased muscle mass and muscle quality. Low-intensity pulsed ultrasound (LIPUS) is an acoustic wave inducing biological effects mainly by the mechanical stimulation and used as a non-invasive physical therapy for muscle repair. Parathyroid hormone (PTH) is an 84-amino-acid polypeptide, and its bioactive fragment [PTH (1-34)] has potential application in the treatment of MA. We speculate that the combination of physical therapy (i.e., the LIPUS) and regulatory hormone (i.e., the PTH) would be more effective in the treatment of MA. The objective of this study was to evaluate the individual and combined effects of LIPUS and PTH therapy on MA in estrogen deficiency mice. Seventy 8-week-old female C57BL/6J mice were used in this study and the MA model was induced by an intraperitoneal injection of 4-vinylcyclohexene diepoxide (VCD) for 20 consecutive days. The VCD-induced MA mice were randomly divided into MA, LIPUS, PTH and LIPUS + PTH (Combined) groups (n = 10/group). In the LIPUS group, the mice were treated by LIPUS in bilateral quadriceps muscles for 20 min, five times a week for 6 weeks. In the PTH group, the mice received subcutaneous injection of PTH (1-34) (80 ug/kg/d) five times a week, for 6 weeks. In the Combined group, the PTH was administrated 30 min before each LIPUS session. Hematoxylin-eosin (H&E) staining, serum biochemical analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were applied to evaluate the therapeutic effects of related treatments. The results showed that the MA mice had a disordered estrus cycle, significantly decreased muscle mass and myofibers cross-sectional area (CSA). After treatments, LIPUS, PTH and Combined groups had a significantly increased CSA, compared with the MA mice without treatment. In addition, Combined group had a significantly increased mRNA expression of Pax7, MyoD and MyoG, compared with LIPUS and PTH monotherapy groups. Our findings indicated that the combination of LIPUS and PTH treatment improves muscle regeneration ability, which might have potential for treating MA in postmenopausal women.

Printed dry electrode for neuromuscular electrical stimulation (NMES) for e-textile.

Muscle atrophy is a well-known consequence of immobilization and critical illness, leading to prolonged rehabilitation and increased mortality. In this study, we develop a solution to preserve muscle mass using customized biocompatible neuromuscular electrical stimulation (NMES) device. Commercially available NMES solutions with gel-based electrodes often lead to skin irritation. We demonstrate the printing of conducting electrodes on a compressive stocking textile that can be used for more than seven days without observing any inflammation. This solution consists of a dry and biocompatible electrode directly integrated into the textile with good mechanical compatibility with skin (Young's modulus of 0.39 MPa). The surface roughness of the underlying substrate plays a significant role in obtaining good print quality. Electrochemical Impedance Spectroscopy (EIS) analysis showed that the printed electrode showed better performance than the commercial ones based on a matched interfacial performance and improved series resistance. Furthermore, we investigated our NMES solution in a hospital setting to evaluate its effectiveness on muscle atrophy, with promising results.

Molecular mechanisms of post-burn muscle wasting and the therapeutic potential of physical exercise.

After a severe burn injury, a systemic stress response activates metabolic and inflammatory derangements that, among other, leads to muscle mass loss (muscle wasting). These negative effects on skeletal muscle continue for several months or years and are aggravated by short-term and long-term disuse. The dynamic balance between muscle protein synthesis and muscle protein breakdown (proteolysis) is regulated by complex signalling pathways that leads to an overall negative protein balance in skeletal muscle after a burn injury. Research concerning these molecular mechanisms is still scarce and inconclusive, understanding of which, if any, molecular mechanisms contribute to muscle wasting is of fundamental importance in designing of therapeutic interventions for burn patients as well. This review not only summarizes our present knowledge of the molecular mechanisms that underpin muscle protein balance but also summarizes the effects of exercise on muscle wasting post-burn as promising strategy to counteract the detrimental effects on skeletal muscle. Future research focusing on the pathways causing post-burn muscle wasting and the different effects of exercise on them is needed to confirm this hypothesis and to lay the foundation of therapeutic strategies.

Mesenchymal stromal cells ameliorate diabetes-induced muscle atrophy through exosomes by enhancing AMPK/ULK1-mediated autophagy.

BACKGROUND: Diabetes and obesity are associated with muscle atrophy that reduces life quality and lacks effective treatment. Mesenchymal stromal cell (MSC)-based therapy can ameliorate high fat-diet (HFD) and immobilization (IM)-induced muscle atrophy in mice. However, the effect of MSCs on muscle atrophy in type 2 diabetes mellitus (T2DM) and the potential mechanism is unclear. Here, we evaluated the efficacy and explored molecular mechanisms of human umbilical cord MSCs (hucMSCs) and hucMSC-derived exosomes (MSC-EXO) on diabetes- and obesity-induced muscle atrophy. METHODS: Diabetic db/db mice, mice fed with high-fat diet (HFD), mice with hindlimb immobilization (IM), and C2C12 myotubes were used to explore the effect of hucMSCs or MSC-EXO in alleviating muscle atrophy. Grip strength test and treadmill running were used to measure skeletal muscle strength and performance. Body composition, muscle weight, and muscle fibre cross-sectional area (CSA) was used to evaluate muscle mass. RNA-seq analysis of tibialis anterior (TA) muscle and Western blot analysis of muscle atrophy signalling, including MuRF1 and Atrogin 1, were performed to investigate the underlying mechanisms. RESULTS: hucMSCs increased grip strength (P = 0.0256 in db/db mice, P = 0.012 in HFD mice, P = 0.0097 in IM mice), running endurance (P = 0.0154 in HFD mice, P = 0.0006 in IM mice), and muscle mass (P = 0.0004 in db/db mice, P = 0.0076 in HFD mice, P = 0.0144 in IM mice) in all models tested, with elevated CSA of muscle fibres (P < 0.0001 in db/db mice and HFD mice, P = 0.0088 in IM mice) and reduced Atrogin1 (P = 0.0459 in db/db mice, P = 0.0088 in HFD mice, P = 0.0016 in IM mice) and MuRF1 expression (P = 0.0004 in db/db mice, P = 0.0077 in HFD mice, P = 0.0451 in IM mice). MSC-EXO replicated all these hucMSC-mediated changes (P = 0.0103 for grip strength, P = 0.013 for muscle mass, P < 0.0001 for CSA of muscle fibres, P = 0.0171 for Atrogin1 expression, and P = 0.006 for MuRF1 expression). RNA-seq revealed that hucMSCs activated the AMPK/ULK1 signalling and enhanced autophagy. Knockdown of AMPK or inhibition of autophagy with 3-methyladenine (3-MA) diminished the beneficial anti-atrophy effects of hucMSCs or MSC-EXO. CONCLUSIONS: Our results suggest that human umbilical cord mesenchymal stromal cells mitigate diabetes- and obesity-induced muscle atrophy via enhancing AMPK/ULK1-mediated autophagy through exosomes, with implications of applying hucMSCs or hucMSC-derived exosomes to treat muscle atrophy.