Mechanisms Of Muscle Atrophy Research Articles

EIF4A3-Induced Circular RNA CircDdb1 Promotes Muscle Atrophy through Encoding a Novel Protein CircDdb1-867aa.

Little is known about if and how circular RNAs (circRNAs) are involved in skeletal muscle atrophy. Here a conserved circular RNA Damage-specific DNA binding protein 1 (circDdb1), derived from the host gene encoding Damage-specific DNA binding protein 1 (DDB1), as a mechanism of muscle atrophy is identified. circDdb1 expression is markedly increased in a variety of muscle atrophy types in vivo and in vitro, and human aging muscle. Both in vivo and in vitro, ectopic expression of circDdb1 causes muscle atrophy. In contrast, multiple forms of muscle atrophy caused by dexamethasone, tumor necrosis factor-alpha (TNF-α), or angiotensin II (Ang II) in myotube cells, as well as by denervation, angiotensin II, and immobility in mice, are prevented by circDdb1 inhibition. Eukaryotic initiation factor 4A3 (EIF4A3) is identified as a regulator of circDdb1 expression in muscle atrophy, whereas circDdb1 encodes a novel protein, circDdb1-867aa. circDdb1-867aa binds with and increases the phosphorylation level of eukaryotic elongation factor 2 (eEF2) at Thr56 to reduce protein translation and promote muscle atrophy. In summary, these findings establish circDdb1 as a shared regulator of muscle atrophy across multiple diseases and a potential therapeutic target.

Report and Abstracts of the 20th Meeting of IIM, the Interuniversity Institute of Myology: Assisi, October 12-15, 2023.

The 2023 represented a milestone for the Interuniversity Institute of Myology (IIM) since it marked twenty years of IIM activity joined with the 20th annual meeting organized by the association. The 20th IIM meeting took place in the fascinating town of Assisi, in the heart of central Italy, from 12 to 15 October. The commemorative 20th edition of the meeting represented a success in terms of participation and contributions as it brought together 160 myologists, clinicians, pharmaceutical companies, and patient organization representatives from Italy, several European countries (especially France), the United Kingdom, Brazil, and the USA. Four main scientific sessions hosted 36 oral communications and 54 always-on-display posters reporting original and unpublished results. Four main lectures from internationally renowned invited speakers and talks from delegates of the Societé Française de Myologie gave particular interest and emphasis to the scientific discussion. In line with the traditional policy of the IIM to encourage the participation of young researchers, about 50% of the attendees were under 35 years old. Moreover, the 20th IIM meeting was part of the high-training course in "Advanced Myology Update 2023", reserved to young trainees and managed by the University of Perugia (Italy) in collaboration with the IIM. In addition to the meeting scientific sessions, the 29 attendees to the course had a dedicated round table and dedicated lessons with the IIM invited speakers as teachers. Awards for the best talk, best poster blitz, and best poster have been conferred to young attendees, who became part of the IIM Young Committee, involved in the scientific organization of the IIM meetings. To celebrate the 20th IIM anniversary, a special free-access educational convention on "Causes and mechanisms of muscle atrophy. From terrestrial disuse to Space flights" has been organized, in which IIM experts in the field have illustrated the current knowledge about the muscle atrophy process in several atrophying conditions, and the former Italian astronaut, Paolo Nespoli shared his incredible experience in Space fascinating the large audience attending both in presence and online live stream. The meeting was characterized by a vibrant, friendly, and inclusive atmosphere, and stimulated discussion on emerging areas of muscle research, fostering international collaborations, and confirming the IIM meeting as an ideal venue to discuss around muscle development, function, and diseases pointing to the development of efficacious therapeutic strategies. Here, the abstracts of the meeting illustrate the most recent results on basic, translational, and clinical research in the myology field. Some abstracts are missing as per authors' decision due to the patentability of the results.

PI3K/AKT/FOXO3a Pathway Induces Muscle Atrophy by Ubiquitin-Proteasome System and Autophagy System in COPD Rat Model.

Muscle atrophy is a common extrapulmonary co-morbidity affecting about 20% of patients with COPD. However, the mechanism of muscle atrophy in COPD remains unclear. This study investigated the role of the ubiquitin-proteasome system (UPS) and the autophagy system in COPD muscle atrophy and its mechanism. A COPD rat model was established to evaluate the in vitro effects of the UPS and the autophagy system in muscle atrophy. In addition, the role of the UPS, autophagy systems, and the expressions of the PI3K/AKT/FOXO3a pathway were studied in the CSE-induced L6 myoblast cells. Furthermore, we evaluated the effect of FOXO3a in the CSE-induced L6 myoblast cells using siRNA-FOXO3a. The results showed that the expression of ubiquitin-related proteins and autophagy-related proteins were significantly increased in the COPD rat model and CSE-induced L6 myoblast cells. At the same time, there was a concurrent decrease in the phosphorylation protein expression of PI3K and AKT, but the transcriptional activity of FOXO3a was increased in CSE-induced L6 myoblast cells. And siRNA-FOXO3a significantly decreased the expression level of the UPS and the autophagy system in CSE-induced L6 myoblast cells. These results suggest that PI3K/AKT/FOXO3a participates in COPD muscle atrophy by regulating the UPS and the autophagy systems.

The effect of tenotomy, neurotomy, and dual injury on mouse rotator cuff muscles: Consequences for the mouse as a preclinical model.

A common animal model of muscle pathology following rotator cuff tear (RCT) is a tenotomy of the supraspinatus and infraspinatus, often combined with neurotomy of the suprascapular nerve, which induces a more robust atrophy response than tenotomy alone. However, the utility of this model depends on its similarity to human muscle pathology post-RCT, both in terms of the disease phenotype and mechanisms of muscle atrophy and fatty infiltration. Given the clinical prevalence of nerve injury is low and the muscular response to denervation is distinct from mechanical unloading in other models, an understanding of the biological influence of the nerve injury is critical for interpreting data from this RCT model. We evaluated the individual and combined effect of tenotomy and neurotomy across multiple biological scales, in a robust time-series in the mouse supraspinatus. Muscle composition, histological, and gene expression data related to muscle atrophy, degeneration-regeneration, fatty infiltration, and fibrosis were evaluated. Broadly, we found tenotomy alone caused small, transient changes in these pathological features, which resolved over the course of the study, while neurotomy alone caused a significant fatty atrophy phenotype. The dual injury group had a similar fatty atrophy phenotype to the neurotomy group, though the addition of tenotomy did marginally enhance the fat and connective tissue. Overall, these results suggest the most clinically relevant injury model, tenotomy alone, does not produce a clinically relevant phenotype. The dual injury model partially recapitulates the human condition, but it does so through a nerve injury, which is not well justified clinically.

An Inquiry into the Role of Muscle Atrophy in Rheumatoid Arthritis and Current Treatment Scenario

Around the world, 0.5 to 1% of adults suffer from rheumatoid arthritis. It is a chronic autoimmune inflammatory illness distinguished by inflammation of hands, knees, wrists, and feet, causing bone and cartilage degradation, joint deformity, and muscle atrophy and thus movement limitations. Inflammatory mediators like necrosis factor and interleukins along with other inflammatory cytokines, execute a vital role in the initiation and advancement of rheumatoid arthritis (RA) as well as muscle atrophy. Existing literature discusses extensively the RA condition. However, the muscle atrophy related to this condition has received little attention, despite the substantial role of muscle atrophy in morbidity caused by RA. The review aims to highlight the relationship between muscle atrophy and RA, the mechanisms of muscle atrophy in RA and the association between oxidative stress and muscle atrophy in RA. This review will be useful for getting insights into the etiopathogenesis of muscle atrophy brought on by rheumatoid arthritis and available treatment alternatives for RA and muscle atrophy caused by RA. Discussion on the potential therapeutic targets and agents to treat skeletal muscle atrophy will help advance the knowledge to improve the condition of muscle atrophy associated with RA.

Impact of Counseling on Patient Education and Dietary in Quality of Lifestyle and Nutritional Anemia in Diabetes Mellitus Patient: A Case-Control Study

The study’s goal was to see how w education and dietary guidance improved the quality of lifestyle and nutritional anemia in people with diabetes type 2. This 6 month prospective study was conducted in a hospital in Jaipur, Rajasthan. The demographic information (age, gender, social position, and economic status) was gathered using a form HRQoL after gaining the patient’s assent. In the intervention group n is 21 and also in the control group n is 21 so the total; patient was chosen 42. The baseline Hb and health-related quality score were taken in consideration in 1, 2 and baseline visits in a month-long study as a part of the design. Each visit concluded with the measurement of the hemoglobin level and health-related quality of life scores for both the intervention and control groups. The intervention group’s Hblevel changed significantly more than the control group’s after the nutrition education intervention finished [0.56–0.40 vs. 0.16–0.82 gm/dl, p = 0.002]. In contrast to the control group, where the mean increase in general health from baseline to second follow-up was statistically insignificant, the intervention group’s mean increase in general health from baseline to second follow-up was found to be significant as from the result obtained. Thus, nutrition education was found to be substantially linked to higher Hb levels, better dietary consumption, and improved health-related quality.mmune inflammatory illness distinguished by inflammation of hands, knees, wrists, and feet, causing bone and cartilage degradation, joint deformity, and muscle atrophy and thus movement limitations. Inflammatory mediators like necrosis factor and interleukins along with other inflammatory cytokines, execute a vital role in the initiation and advancement of rheumatoid arthritis (RA) as well as muscle atrophy. Existing literature discusses extensively the RA condition. However, the muscle atrophy related to this condition has received little attention, despite the substantial role of muscle atrophy in morbidity caused by RA. The review aims to highlight the relationship between muscle atrophy and RA, the mechanisms of muscle atrophy in RA and the association between oxidative stress and muscle atrophy in RA. This review will be useful for getting insights into the etiopathogenesis of muscle atrophy brought on by rheumatoid arthritis and available treatment alternatives for RA and muscle atrophy caused by RA. Discussion on the potential therapeutic targets and agents to treat skeletal muscle atrophy will help advance the knowledge to improve the condition of muscle atrophy associated with RA.

Integrating Mechanisms of Exacerbated Atrophy and Other Adverse Skeletal Muscle Impact in COPD.

The normal decline in skeletal muscle mass that occurs with aging is exacerbated in patients with chronic obstructive pulmonary disease (COPD) and contributes to poor health outcomes, including a greater risk of death. There has been controversy about the causes of this exacerbated muscle atrophy, with considerable debate about the degree to which it reflects the very sedentary nature of COPD patients vs. being precipitated by various aspects of the COPD pathophysiology and its most frequent proximate cause, long-term smoking. Consistent with the latter view, recent evidence suggests that exacerbated aging muscle loss with COPD is likely initiated by decades of smoking-induced stress on the neuromuscular junction that predisposes patients to premature failure of muscle reinnervation capacity, accompanied by various alterations in mitochondrial function. Superimposed upon this are various aspects of COPD pathophysiology, such as hypercapnia, hypoxia, and inflammation, that can also contribute to muscle atrophy. This review will summarize the available knowledge concerning the mechanisms contributing to exacerbated aging muscle affect in COPD, consider the potential role of comorbidities using the specific example of chronic kidney disease, and identify emerging molecular mechanisms of muscle impairment, including mitochondrial permeability transition as a mechanism of muscle atrophy, and chronic activation of the aryl hydrocarbon receptor in driving COPD muscle pathophysiology.

Impaired expression of BCAT1 relates to muscle atrophy of mouse model of sarcopenia

BackgroundThe underlying mechanism of muscle atrophy in sarcopenia is still not fully understood; branched chain aminotransferase 1(BCAT1) isocitrate dehydrogenase-1 encodes an evolutionarily conserved cytoplasmic aminotransferase for glutamate and branched-chain amino acids (BCAAs), thus constituting a regulatory component of cytoplasmic amino and keto acid metabolism. In human gliomas carrying wild-type isocitrate dehydrogenase-1, BCAT1 promotes cell proliferation through amino acid catabolism. Hence, the goals of this study were to unravel the potential role of BCAT1 expression in muscle atrophy and to explore the mechanisms underlying this process.MethodsWe first measured Bcat1 expression by RT-qPCR and western blotting in murine and cellular models of muscle atrophy. To understand how the Bcat1-driven changes sustained muscle cell growth, we analyzed reactive oxygen species (ROS) levels and activation of the mTORC1/S6K1 pathway in muscle cells. Furthermore, we performed Cell Counting Kit-8(CCK8) assays and fluorescence staining to evaluate growth rate of cells and ROS levels. Finally, we verified that depletion of Bcat1 impairs the growth rate of muscle cells and increases ROS levels, indicating that muscle atrophy resulted from the downregulation of the mTORC1/S6K1 pathway. Data were analyzed by two-tailed unpaired Student’s t-test or Mann-Whitney U test for two groups to determine statistical significance. Statistical analyses were performed using GraphPad Prism version 6.0 and SPSS 16.0 software.ResultsBcat1 expression level in skeletal muscles was lower in murine and cellular models of sarcopenia than in the control groups. Bcat1 knockdown not only suppressed the growth of muscle cells but also increased the production of ROS. Impaired cell growth and increased ROS production was rescued by co-introduction of an shRNA-resistant Bcat1 cDNA or addition of the mTORC1 stimulator MYH1485. Muscle cells with Bcat1 knockdown featured lower mTORC1 and S6K1 phosphorylation (pS6K1) than NT muscle cells. Addition of either shRNA-resistant Bcat1 cDNA or MYH1485 rescued the suppression of cell growth, increase in ROS production, and decrease in pS6K1.ConclusionsThe branched chain amino acids catabolic enzyme BCAT1 is essential for the growth of muscle cells. BCAT1 expression contributes to sustained growth of muscle cells by activating mTOR signaling and reducing ROS production.

Bioinformatic analysis of the gene expression profile in muscle atrophy after spinal cord injury

Spinal cord injury (SCI) is often accompanied by muscle atrophy; however, its underlying mechanisms remain unclear. Here, the molecular mechanisms of muscle atrophy following SCI were investigated. The GSE45550 gene expression profile of control (before SCI) and experimental (14 days following SCI) groups, consisting of Sprague–Dawley rat soleus muscle (n = 6 per group), was downloaded from the Gene Expression Omnibus database, and then differentially expressed gene (DEG) identification and Gene Ontology, pathway, pathway network, and gene signal network analyses were performed. A total of 925 differentially expressed genes, 149 biological processes, and 55 pathways were screened. In the pathway network analysis, the 10 most important pathways were citrate cycle (TCA cycle), pyruvate metabolism, MAPK signalling pathway, fatty acid degradation, propanoate metabolism, apoptosis, focal adhesion, synthesis and degradation of ketone bodies, Wnt signalling, and cancer pathways. In the gene signal network analysis, the 10 most important genes were Acat1, Acadvl, Acaa2, Hadhb, Acss1, Oxct1, Hadha, Hadh, Acaca, and Cpt1b. Thus, we screened the key genes and pathways that may be involved in muscle atrophy after SCI and provided support for finding valuable markers for this disease.

Identification of potential microRNAs and KEGG pathways in denervation muscle atrophy based on meta-analysis

The molecular mechanism of muscle atrophy has been studied a lot, but there is no comprehensive analysis focusing on the denervated muscle atrophy. The gene network that controls the development of denervated muscle atrophy needs further elucidation. We examined differentially expressed genes (DEGs) from five denervated muscle atrophy microarray datasets and predicted microRNAs that target these DEGs. We also included the differentially expressed microRNAs datasets of denervated muscle atrophy in previous studies as background information to identify potential key microRNAs. Finally, we compared denervated muscle atrophy with disuse muscle atrophy caused by other reasons, and obtained the Den-genes which only differentially expressed in denervated muscle atrophy. In this meta-analysis, we obtained 429 up-regulated genes, 525 down-regulated genes and a batch of key microRNAs in denervated muscle atrophy. We found eight important microRNA-mRNA interactions (miR-1/Jun, miR-1/Vegfa, miR-497/Vegfa, miR-23a/Vegfa, miR-206/Vegfa, miR-497/Suclg1, miR-27a/Suclg1, miR-27a/Mapk14). The top five KEGG pathways enriched by Den-genes are Insulin signaling pathway, T cell receptor signaling pathway, MAPK signaling pathway, Toll-like receptor signaling pathway and B cell receptor signaling pathway. Our research has delineated the RNA regulatory network of denervated muscle atrophy, and uncovered the specific genes and terms in denervated muscle atrophy.

Differential Protein Metabolism and Regeneration in Gastrocnemius Muscles in High-fat Diet Fed Mice and Pre-hibernation Daurian Ground Squirrels: A Comparison between Pathological and Healthy Obesity.

We focused on pathological obesity induced by excessive fat intake (nutritional obesity) in non-hibernator and healthy obesity due to pre-hibernation (PRE) fat storage in hibernator to study the effects of different types of obesity on skeletal muscle protein metabolism and cell regeneration. Kunming mice were fed with high-fat diet for 3 months to construct a pathological obesity model. Daurian ground squirrels fattened naturally before hibernation were used as a healthy obesity model. Body weight, adipose tissue wet weight, gastrocnemius muscle wet weight, muscle fiber cross-sectional area (CSA) and fiber type distribution were measured. The protein expression levels related to protein degradation (MuRF-1, atrogin-1, calpain1, calpain2, calpastatin, desmin, troponin T, Beclin-1, LC3-II), protein synthesis (P-Akt, P-mTORC1, P-S6K1, P-4E-BP1) and cell regeneration (MyoD, myogenin, myostatin) were detected by Western blot. As a result, the body weight and adipose tissue wet weight were both significantly increased in high fat obese (OB) mice and pre-hibernation fat (PRE) ground squirrels. The muscle wet weight, ratio of muscle wet weight to body weight, and muscle fiber CSA were significantly decreased, while the percentage of MHC I fiber isoform was significantly increased in gastrocnemius muscle of OB mice compared with the control (CON) group. The protein expression levels of P-Akt, P-mTORC1, P-4E-BP1 and myogenin were significantly decreased, while those of calpain1, calpain2, MuRF-1 and myostatin were significantly increased in the OB mice. In the ground squirrels, the muscle wet weight, muscle fiber CSA and percentage of MHC I fiber isoform all showed no change in the gastrocnemius muscle in the PRE group compared with the summer active (SA) group. The protein expression levels of P-Akt, P-mTORC1, P-S6K1 and MyoD were significantly increased, while those of Beclin-1 and LC3-II were significantly decreased in the PRE ground squirrels. This study demonstrated that the decrease in protein expression levels in the Akt/mTOR pathway (P-Akt, P-mTORC1 and P-4E-BP1) and cell regeneration (myogenin) and the increase in protein expression levels of the calpain pathway (calpain1 and calpain2) and ubiquitin-proteasome pathway (MuRF-1) were involved in the mechanism of muscle atrophy in gastrocnemius muscle of the pathologically obese Kunming mice induced by high-fat diet. In contrast, the increased protein expression levels of the Akt/mTOR pathway (P-Akt, P-mTORC1 and P-S6K1) and cell regeneration (MyoD), and the decreased protein expression levels of the autophagy lysosomal pathway (Beclin-1 and LC3-II) were involved in the mechanism of anti-atrophy in gastrocnemius muscle of the healthy obese ground squirrels fattened before hibernation.

Increased Adenine Nucleotide Degradation in Skeletal Muscle Atrophy.

Adenine nucleotides (AdNs: ATP, ADP, AMP) are essential biological compounds that facilitate many necessary cellular processes by providing chemical energy, mediating intracellular signaling, and regulating protein metabolism and solubilization. A dramatic reduction in total AdNs is observed in atrophic skeletal muscle across numerous disease states and conditions, such as cancer, diabetes, chronic kidney disease, heart failure, COPD, sepsis, muscular dystrophy, denervation, disuse, and sarcopenia. The reduced AdNs in atrophic skeletal muscle are accompanied by increased expression/activities of AdN degrading enzymes and the accumulation of degradation products (IMP, hypoxanthine, xanthine, uric acid), suggesting that the lower AdN content is largely the result of increased nucleotide degradation. Furthermore, this characteristic decrease of AdNs suggests that increased nucleotide degradation contributes to the general pathophysiology of skeletal muscle atrophy. In view of the numerous energetic, and non-energetic, roles of AdNs in skeletal muscle, investigations into the physiological consequences of AdN degradation may provide valuable insight into the mechanisms of muscle atrophy.

Asparagine reduces the mRNA expression of muscle atrophy markers via regulating protein kinase B (Akt), AMP-activated protein kinase α, toll-like receptor 4 and nucleotide-binding oligomerisation domain protein signalling in weaning piglets after lipopolysaccharide challenge.

Pro-inflammatory cytokines are critical in mechanisms of muscle atrophy. In addition, asparagine (Asn) is necessary for protein synthesis in mammalian cells. We hypothesised that Asn could attenuate lipopolysaccharide (LPS)-induced muscle atrophy in a piglet model. Piglets were allotted to four treatments (non-challenged control, LPS-challenged control, LPS+0·5 % Asn and LPS+1·0 % Asn). On day 21, the piglets were injected with LPS or saline. At 4 h post injection, piglet blood and muscle samples were collected. Asn increased protein and RNA content in muscles, and decreased mRNA expression of muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1). However, Asn had no effect on the protein abundance of MAFbx and MuRF1. In addition, Asn decreased muscle AMP-activated protein kinase (AMPK) α phosphorylation, but increased muscle protein kinase B (Akt) and Forkhead Box O (FOXO) 1 phosphorylation. Moreover, Asn decreased the concentrations of TNF-α, cortisol and glucagon in plasma, and TNF-α mRNA expression in muscles. Finally, Asn decreased mRNA abundance of muscle toll-like receptor (TLR) 4 and nucleotide-binding oligomerisation domain protein (NOD) signalling-related genes, and regulated their negative regulators. The beneficial effects of Asn on muscle atrophy may be associated with the following: (1) inhibiting muscle protein degradation via activating Akt and inactivating AMPKα and FOXO1; and (2) decreasing the expression of muscle pro-inflammatory cytokines via inhibiting TLR4 and NOD signalling pathways by modulation of their negative regulators.

Transcriptional activator TAp63 is upregulated in muscular atrophy during ALS and induces the pro-atrophic ubiquitin ligase Trim63.

Mechanisms of muscle atrophy are complex and their understanding might help finding therapeutic solutions for pathologies such as amyotrophic lateral sclerosis (ALS). We meta-analyzed transcriptomic experiments of muscles of ALS patients and mouse models, uncovering a p53 deregulation as common denominator. We then characterized the induction of several p53 family members (p53, p63, p73) and a correlation between the levels of p53 family target genes and the severity of muscle atrophy in ALS patients and mice. In particular, we observed increased p63 protein levels in the fibers of atrophic muscles via denervation-dependent and -independent mechanisms. At a functional level, we demonstrated that TAp63 and p53 transactivate the promoter and increased the expression of Trim63 (MuRF1), an effector of muscle atrophy. Altogether, these results suggest a novel function for p63 as a contributor to muscular atrophic processes via the regulation of multiple genes, including the muscle atrophy gene Trim63.

Botulinum Toxin and Muscle Atrophy: A Wanted or Unwanted Effect.

While the facial rejuvenating effect of botulinum toxin type A is well known and widespread, its use in body and facial contouring is less common. We first describe its use for deliberate muscle volume reduction, and then document instances of unanticipated and undesirable muscle atrophy. Finally, we investigate the potential long-term adverse effects of botulinum toxin-induced muscle atrophy. Although the use of botulinum toxin type A in the cosmetic patient has been extensively studied, there are several questions yet to be addressed. Does prolonged botulinum toxin treatment increase its duration of action? What is the mechanism of muscle atrophy and what is the cause of its reversibility once treatment has stopped? We proceed to examine how prolonged chemodenervation with botulinum toxin can increase its duration of effect and potentially contribute to muscle atrophy. Instances of inadvertent botulinum toxin-induced atrophy are also described. These include the "hourglass deformity" secondary to botulinum toxin type A treatment for migraine headaches, and a patient with atrophy of multiple facial muscles from injections for hemifacial spasm. Numerous reports demonstrate that muscle atrophy after botulinum toxin type A treatment occurs and is both reversible and temporary, with current literature supporting the notion that repeated chemodenervation with botulinum toxin likely responsible for both therapeutic and incidental temporary muscle atrophy. Furthermore, duration of response may be increased with subsequent treatments, thus minimizing frequency of reinjection. Practitioners should be aware of the temporary and reversible effect of botulinum toxin-induced muscle atrophy and be prepared to reassure patients on this matter.

Fibrosis, adipogenesis, and muscle atrophy in congenital muscular torticollis.

In the traditional view, muscle atrophy and interstitial fibrosis were regarded as the basic pathological features of congenital muscular torticollis (CMT). But in the ultrastructure study, the mesenchyme-like cells, myoblasts, myofibroblasts, and fibroblasts were found in the proliferation of interstitium of CMT. To investigate the characteristics of pathological features and the mechanisms of muscle atrophy in CMT, we retrospectively reviewed the medical records of 185 CMT patients from July 2009 to July 2011 in Shenzhen Children's Hospital in China and performed pathological studies. According to age, the 185 CMT patients were divided into 4 groups. All resected surgical specimens were processed for hematoxylin and eosin staining and Masson trichromic staining. Sudan III staining was used for frozen sections, whereas immunohistochemical staining for S-100, calpain-1, ubiquitin, and 20S proteasome was carried out on 40 CMT specimens. Eight adductor muscle specimens from 8 patients with development dysplasia of the hip were taken as control group in the immunohistochemical staining. By Masson trichromic staining, the differences in the percent area of fibrous tissue in each CMT groups were significant. In Sudan III staining and immunostaining for S-100, adipocyte hyperplasia was the pathological feature of CMT. Moreover, compared with controls, most atrophic muscle fibers in CMT specimens were found to show strong immunoreactivity for calpain-1, ubiquitin, and 20S proteasome. With increasing age, fibrosis peaked at both sides and it was low in middle age group. Adipocytes increased with age. The characteristics of pathological features in CMT are changeable with age. The calpain and the ubiquitin–proteasome system may play a role in muscle atrophy of CMT. In the CMT, adipogenesis, fibrogenesis, and myogenesis may be the results of mesenchyme-like cells in SCM (sternocleidomastoid muscle). In conclusion, the present study furthermore supports maldevelopment of the fetal SCM theory for etiology of CMT.

Paper 79: Semitendinosus Tendon Regeneration after ACL Reconstruction: A Morphological and Functional Study

Paper 79: Semitendinosus Tendon Regeneration after ACL Reconstruction: A Morphological and Functional Study

Differential features of muscle fiber atrophy in osteoporosis and osteoarthritis

SummaryWe demonstrated that osteoporosis is associated with a preferential type II muscle fiber atrophy, which correlates with bone mineral density and reduced levels of Akt, a major regulator of muscle mass. In osteoarthritis, muscle atrophy is of lower extent and related to disease duration and severity.IntroductionOsteoarthritis (OA) and osteoporosis (OP) are associated with loss of muscle bulk and power. In these diseases, morphological studies on muscle tissue are lacking, and the underlying mechanisms of muscle atrophy are not known. The aim of our study was to evaluate the OP- or OA-related muscle atrophy and its correlation with severity of disease. Muscle levels of Akt protein, a component of IGF-1/PI3K/Akt pathway, the main regulator of muscle mass, have been determined.MethodsWe performed muscle biopsy in 15 women with OP and in 15 women with OA (age range, 60–85 years). Muscle fibers were counted, measured, and classified by ATPase reaction. By statistical analysis, fiber-type atrophy was correlated with bone mineral density (BMD) in the OP group and with Harris Hip Score (HHS) and disease duration in the OA group. Akt protein levels were evaluated by Western blot analysis.ResultsOur findings revealed in OP a preferential type II fiber atrophy that inversely correlated with patients’ BMD. In OA, muscle atrophy was of lower extent, homogeneous among fiber types and related to disease duration and HHS. Moreover, in OP muscle, the Akt level was significantly reduced as compared to OA muscles.ConclusionsThis study shows that in OP, there is a preferential and diffuse type II fiber atrophy, proportional to the degree of bone loss, whereas in OA, muscle atrophy is connected to the functional impairment caused by the disease. A reduction of Akt seems to be one of the mechanisms involved in OP-related muscle atrophy.

Molecular mechanism of unloading-mediated muscle atrophy and development of its countermeasures

The ubiquitin ligase Cbl-b plays a major role in skeletal muscle atrophy induced by unloading [1]. The mechanism of Cbl-b-induced muscle atrophy is unique in that it does not appear to involve the degradation of structural components of the muscle, but rather it impairs muscular trophic signals in response to unloading conditions. Recent studies on the molecular mechanisms of muscle atrophy have focused on the role of IGF-1/PI3K/Akt-1 signaling cascade as a vital pathway in the regulation of the balance between hypertrophy and atrophy [2,3]. These studies indicate that under muscle wasting conditions, such as disuse, diabetes and fasting, decreased IGF-1/PI3K/Akt-1 signaling augments the expression of atrogin-1, resulting in muscle atrophy. However, these studies did not address the mechanisms of unloading-induced impairment of growth factor signaling. In the present study, we found that under both in vitro and in vivo experimental conditions, Cbl-b ubiquitinated and induced specific degradation of IRS-1, a key intermediate of skeletal muscle growth regulated by IGF-1/insulin and growth hormone, resulting in inactivation of Akt-1. Inactivation of Akt-1 led to upregulation of atrogin-1 through dephosphorylation (activation) of FOXO3, as well as reduced mitogen response, in skeletal muscle. Thus, activation of Cbl-b may be an important mechanism underlying the failure of atrophic muscle to respond to growth factor-based treatments such as IGF-1 (Figure ​(Figure11). Figure 1 Possible mechanism of unloading-mediated muscle atrophy.

Myosin heavy chain is not selectively decreased in murine cancer cachexia

Cachexia is a severe muscle-wasting syndrome associated with several chronic diseases such as cancer and AIDS. Muscle mass loss significantly decreases prognosis and survival. The mechanisms of muscle atrophy and the specific proteins targeted for degradation have been intensely studied and are potential therapeutic targets. Published reports that myosin heavy chain (MyHC), the most abundant protein by mass in skeletal muscle, is selectively targeted for degradation in cancer cachexia remain controversial. Here we show that the results of previous studies showing a selective decrease in MyHC are likely an artifact resulting from muscle lysis methods which do not solubilize myosin out of myofibrils. We show that MyHC decreases in parallel with other myofibrillar proteins in cachectic skeletal muscle, which has mechanistic and therapeutic implications. These findings should lead to mechanistic insight into the stoichiometry of sarcomeric disassembly and degradation during cancer cachexia.