Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and remodeling.

Skeletal muscle atrophy is a morbidity and mortality risk factor that happens with disuse, chronic disease, and aging. The tissue remodeling that happens during recovery from atrophy or injury involves changes in different cell types such as muscle fibers, and satellite and immune cells. Here, we show that the previously uncharacterized gene and protein Zfp697 is a damage-induced regulator of muscle remodeling. Zfp697/ZNF697 expression is transiently elevated during recovery from muscle atrophy or injury in mice and humans. Sustained Zfp697 expression in mouse muscle leads to a gene expression signature of chemokine secretion, immune cell recruitment, and extracellular matrix remodeling. Notably, although Zfp697 is expressed in several cell types in skeletal muscle, myofiber-specific Zfp697 genetic ablation in mice is sufficient to hinder the inflammatory and regenerative response to muscle injury, compromising functional recovery. We show that Zfp697 is an essential mediator of the interferon gamma response in muscle cells and that it functions primarily as an RNA-interacting protein, with a very high number of miRNA targets. This work identifies Zfp697 as an integrator of cell-cell communication necessary for tissue remodeling and regeneration.

Impact of combined intermittent fasting and high-intensity interval training on apoptosis and atrophy signaling in rat fast- and slow-twitch muscles.

This study aimed to evaluate the influence of combined intermittent fasting (IF) and high-intensity interval training (HIIT) on morphology, caspase-independent apoptosis signaling pathway, and myostatin expression in soleus and gastrocnemius (white portion) muscles from healthy rats. Sixty-day-old male Wistar rats (n = 60) were divided into four groups: control (C), IF, high-intensity-interval training (T), and high-intensity-interval training and intermittent fasting (T-IF). The C and T groups received ad libitum chow daily; IF and T-IF received the same standard chow every other day. Animals from T and T-IF underwent a HIIT protocol five times a week for 12 weeks. IF reduced gastrocnemius mass and increased pro-apoptotic proteins apoptosis-inducing factor (AIF) and endonuclease G (EndoG) in soleus and cleaved-to-non-cleaved PARP-1 ratio and myostatin expression in gastrocnemius white portion. HIIT increased AIF and apoptosis repressor with caspase recruitment domain expression in soleus and cleaved-to-total PARP-1 ratio in gastrocnemius muscle white portion. The combination of IF and HIIT reduced fiber cross-sectional area in both muscles, increased EndoG and AIF expression, and decreased cleaved-to-non-cleaved PARP-1 ratio in gastrocnemius muscle white portion. Muscle responses to IF and HIIT are directly impacted by the muscle fiber type composition and are modulated, at least in part, by myostatin and caspase-independent apoptosis signaling.

Apolipoprotein E knockout, but not cholesteryl ester transfer protein (CETP)-associated high-density lipoprotein cholesterol (HDL-C) lowering, exacerbates muscle wasting in dysferlin-null mice.

BACKGROUND: Dysferlin-deficient limb-girdle muscular dystrophy type 2B (Dysf) mice are notorious for their mild phenotype. Raising plasma total cholesterol (CHOL) via apolipoprotein E (ApoE) knockout (KO) drastically exacerbates muscle wasting in Dysf mice. However, dysferlinopathic patients have abnormally reduced plasma high-density lipoprotein cholesterol (HDL-C) levels. The current study aimed to determine whether HDL-C lowering can exacerbate the mild phenotype of dysferlin-null mice. METHODS: Human cholesteryl ester transfer protein (CETP), a plasma lipid transfer protein not found in mice that reduces HDL-C, and/or its optimal adapter protein human apolipoprotein B (ApoB), were overexpressed in Dysf mice. Mice received a 2% cholesterol diet from 2 months of age and characterized through ambulatory and hanging functional tests, plasma analyses, and muscle histology. RESULTS: CETP/ApoB expression in Dysf mice caused reduced HDL-C (54.5%) and elevated ratio of CHOL/HDL-C (181.3%) compared to control Dysf mice in plasma, but without raising CHOL. Compared to the severe muscle pathology found in high CHOL Dysf/ApoE double knockout mice, Dysf/CETP/ApoB mice did not show significant changes in ambulation, hanging capacity, increases in damaged area, collagen deposition, or decreases in cross-sectional area and healthy myofibre coverage. CONCLUSIONS: CETP/ApoB over-expression in Dysf mice decreases HDL-C without increasing CHOL or exacerbating muscle pathology. High CHOL or nonHDL-C caused by ApoE KO, rather than low HDL-C, likely lead to rodent muscular dystrophy phenotype humanization.

Epigenetics of Skeletal Muscle Atrophy.

Skeletal muscle atrophy, characterized by diminished muscle strength and mass, arises from various causes, including malnutrition, aging, nerve damage, and disease-related secondary atrophy. Aging markedly escalates the prevalence of sarcopenia. Concurrently, the incidence of muscle atrophy significantly rises among patients with chronic ailments such as heart failure, diabetes, and chronic obstructive pulmonary disease (COPD). Epigenetics plays a pivotal role in skeletal muscle atrophy. Aging elevates methylation levels in the promoter regions of specific genes within muscle tissues. This aberrant methylation is similarly observed in conditions like diabetes, neurological disorders, and cardiovascular diseases. This study aims to explore the relationship between epigenetics and skeletal muscle atrophy, thereby enhancing the understanding of its pathogenesis and uncovering novel therapeutic strategies.

Exendin-4, a glucagon-like peptide-1 receptor agonist, alleviates muscular dysfunction and wasting in a streptozotocin-induced diabetic mouse model compared to metformin.

Diabetic muscular atrophy is becoming a fast-growing problem worldwide, including sarcopenia, which is associated with substantial mortality and morbidity risk. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been marketed and suggested to exert protective effects on not only glycemic control but also diabetic complications in diabetic patients. In this study, we investigated the therapeutic use of GLP-1RAs exendin-4, compared to antidiabetic drug metformin, for the intervention of muscular dysfunction during diabetic conditions using a streptozotocin (STZ)-induced diabetic mouse model. The results showed that both exendin-4 and metformin could effectively alleviate hyperglycemia in diabetic mice, and also counteract diabetes-induced muscle weight loss, weaker grip, and changes in muscle fiber cross-sectional area distribution. Unexpectedly, exendin-4, but not metformin, enhanced the increased kidney weight and histological change in diabetic mice. Taken together, these findings suggest that both exendin-4 and metformin could effectively improve the diabetic hyperglycemia and muscular dysfunction; but exendin-4 may aggravate the nephropathy in STZ-induced diabetic mice.

Dystrophin S3059 phosphorylation partially attenuates denervation atrophy in mouse tibialis anterior muscles.

The dystrophin protein has well-characterized roles in force transmission and maintaining membrane integrity during muscle contraction. Studies have reported decreased expression of dystrophin in atrophying muscles during wasting conditions, and that restoration of dystrophin can attenuate atrophy, suggesting a role in maintaining muscle mass. Phosphorylation of S3059 within the cysteine-rich region of dystrophin enhances binding between dystrophin and ß-dystroglycan, and mimicking phosphorylation at this site by site-directed mutagenesis attenuates myotube atrophy in vitro. To determine whether dystrophin phosphorylation can attenuate muscle wasting in vivo, CRISPR-Cas9 was used to generate mice with whole body mutations of S3059 to either alanine (DmdS3059A) or glutamate (DmdS3059E), to mimic a loss of, or constitutive phosphorylation of S3059, on all endogenous dystrophin isoforms, respectively. Sciatic nerve transection was performed on these mice to determine whether phosphorylation of dystrophin S3059 could attenuate denervation atrophy. At 14 days post denervation, atrophy of tibialis anterior (TA) but not gastrocnemius or soleus muscles, was partially attenuated in DmdS3059E mice relative to WT mice. Attenuation of atrophy was associated with increased expression of ß-dystroglycan in TA muscles of DmdS3059E mice. Dystrophin S3059 phosphorylation can partially attenuate denervation-induced atrophy, but may have more significant impact in less severe modes of muscle wasting.

The relationship between the duration and the retraction and atrophy grades in traumatic isolated full-thickness supraspinatus tears in young patients.

BACKGROUND: The study aimed to determine the grade of retraction and atrophy according to the time elapsed in traumatic isolated full-thickness supraspinatus (SS) tears in young patients. METHODS: One thousand twenty-six patients, who underwent arthroscopic shoulder surgery, were retrospectively reviewed. Pre-operative magnetic resonance imaging (MRI) of 69 patients aged 18 to 40 years with isolated traumatic full-thickness SS lesions remaining after exclusion criteria were evaluated for tendon retraction and atrophy grades. SS retraction was determined from a T2-weighted oblique coronal MRI slice, and the atrophy grade was determined from the T1-weighted oblique sagittal MRI slice. The patients were divided into four groups 0-1 month, 1-3 months, 3-6 months, and 6-12 months according to the time between trauma and MRI. The relationship of tendon retraction and muscle atrophy with elapsed time was evaluated, in addition, comparisons between groups were made. RESULTS: Thirty-one (45%) of the patients were female and their mean age was 30 ± 7.3 (18-40) years. The mean age of men was 30.5 ± 6.9 (18-39) years (p = 0.880). The time between rupture and MRI was moderately correlated with retraction and strongly correlated with atrophy grades (r = 0.599, 0.751, respectively). It was observed that there was a statistically significant difference between the 1st (0-1 month) and 2nd (1-3 months) groups (p = 0.003, 0.001, respectively), and between the 2nd and 3rd (3-6 months) groups (p = 0.032, 0.002, respectively), but there was no significant difference between the 3rd and 4th (6-12 months) groups (p = 0.118, 0.057, respectively). In addition, there was a moderate correlation between tendon retraction and atrophy grades (r = 0.668). Power (1- b) in post hoc analysis was calculated as 0.826. CONCLUSIONS: The current study, supported by arthroscopy, showed that there is a moderate and strong positive correlation between the time elapsed after trauma and the level of retraction and degree of atrophy in traumatic full-thickness SS tears, and demonstrated the importance of early surgical intervention in young patients.

Epigenetic control of skeletal muscle atrophy.

Skeletal muscular atrophy is a complex disease involving a large number of gene expression regulatory networks and various biological processes. Despite extensive research on this topic, its underlying mechanisms remain elusive, and effective therapeutic approaches are yet to be established. Recent studies have shown that epigenetics play an important role in regulating skeletal muscle atrophy, influencing the expression of numerous genes associated with this condition through the addition or removal of certain chemical modifications at the molecular level. This review article comprehensively summarizes the different types of modifications to DNA, histones, RNA, and their known regulators. We also discuss how epigenetic modifications change during the process of skeletal muscle atrophy, the molecular mechanisms by which epigenetic regulatory proteins control skeletal muscle atrophy, and assess their translational potential. The role of epigenetics on muscle stem cells is also highlighted. In addition, we propose that alternative splicing interacts with epigenetic mechanisms to regulate skeletal muscle mass, offering a novel perspective that enhances our understanding of epigenetic inheritance's role and the regulatory network governing skeletal muscle atrophy. Collectively, advancements in the understanding of epigenetic mechanisms provide invaluable insights into the study of skeletal muscle atrophy. Moreover, this knowledge paves the way for identifying new avenues for the development of more effective therapeutic strategies and pharmaceutical interventions.

AAV-NRIP gene therapy ameliorates motor neuron degeneration and muscle atrophy in ALS model mice.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration, leading to neuromuscular junction (NMJ) dismantling and severe muscle atrophy. The nuclear receptor interaction protein (NRIP) functions as a multifunctional protein. It directly interacts with calmodulin or α-actinin 2, serving as a calcium sensor for muscle contraction and maintaining sarcomere integrity. Additionally, NRIP binds with the acetylcholine receptor (AChR) for NMJ stabilization. Loss of NRIP in muscles results in progressive motor neuron degeneration with abnormal NMJ architecture, resembling ALS phenotypes. Therefore, we hypothesize that NRIP could be a therapeutic factor for ALS. METHODS: We used SOD1 G93A mice, expressing human SOD1 with the ALS-linked G93A mutation, as an ALS model. An adeno-associated virus vector encoding the human NRIP gene (AAV-NRIP) was generated and injected into the muscles of SOD1 G93A mice at 60 days of age, before disease onset. Pathological and behavioral changes were measured to evaluate the therapeutic effects of AAV-NRIP on the disease progression of SOD1 G93A mice. RESULTS: SOD1 G93A mice exhibited lower NRIP expression than wild-type mice in both the spinal cord and skeletal muscle tissues. Forced NRIP expression through AAV-NRIP intramuscular injection was observed in skeletal muscles and retrogradely transduced into the spinal cord. AAV-NRIP gene therapy enhanced movement distance and rearing frequencies in SOD1 G93A mice. Moreover, AAV-NRIP increased myofiber size and slow myosin expression, ameliorated NMJ degeneration and axon terminal denervation at NMJ, and increased the number of α-motor neurons (α-MNs) and compound muscle action potential (CMAP) in SOD1 G93A mice. CONCLUSIONS: AAV-NRIP gene therapy ameliorates muscle atrophy, motor neuron degeneration, and axon terminal denervation at NMJ, leading to increased NMJ transmission and improved motor functions in SOD1 G93A mice. Collectively, AAV-NRIP could be a potential therapeutic drug for ALS.

A Preclinical Model of Sepsis-Induced Myopathy with Disuse in Mice.

Sepsis is a major cause of in-hospital deaths. Improvements in treatment result in a greater number of sepsis survivors. Approximately 75% of the survivors develop muscle weakness and atrophy, increasing the incidence of hospital readmissions and mortality. However, the available preclinical models of sepsis do not address skeletal muscle disuse, a key component for the development of sepsis-induced myopathy. Our objective in this protocol is to provide a step-by-step guideline for a mouse model that reproduces the clinical setting experienced by a bedridden septic patient. Male C57Bl/6 mice were used to develop this model. Mice underwent cecal ligation and puncture (CLP) to induce sepsis. Four days post-CLP, mice were subjected to hindlimb suspension (HLS) for seven days. Results were compared with sham-matched surgeries and/or animals with normal ambulation (NA). Muscles were dissected for in vitro muscle mechanics and morphological assessments. The model results in marked muscle atrophy and weakness, a similar phenotype observed in septic patients. The model represents a platform for testing potential therapeutic strategies for the mitigation of sepsis-induced myopathy.

Dihydromyricetin Inhibits Ferroptosis to Attenuate Cisplatin-Induced Muscle Atrophy.

Cisplatin is a widely used chemotherapy drug for the treatment of various cancers. However, although cisplatin is effective in targeting cancer cells, it has severe side effects including skeletal muscle atrophy. In this study, we aimed to characterize the role of Dihydromyricetin in cisplatin-induced muscle atrophy in mice. 5-week-old male C57BL/6 mice were treated with Dihydromyricetin for 14 days orally followed by in intraperitoneally cisplatin administration for 6 days. Gastrocnemius muscles were isolated for the following experiments. Antioxidative stress were determined by peroxidative product malondialdehyde (MDA) and antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Quadriceps muscle mass and grip strength were significantly restored by Dihydromyricetin in a dose-dependent manner. Moreover, muscle fibers were improved in Dihydromyricetin treated group. Excessive skeletal muscle E3 ubiquitin-protein ligases in cisplatin group were significantly repressed by Dihydromyricetin treatment. Dihydromyricetin significantly reduced oxidative stress induced by cisplatin by decreasing MDA level and restored SOD and GPx activities. In addition, ferroptosis was significantly reduced by Dihydromyricetin characterized by reduced iron level and ferritin heavy chain 1 and improved Gpx4 level. The present study demonstrated that Dihydromyricetin attenuated cisplatin-induced muscle atrophy by reducing skeletal muscle E3 ubiquitin-protein ligases, oxidative stress, and ferroptosis.

Biomechanical effects of deltoid muscle atrophy on rotator cuff tissue: a finite element study.

The deltoid muscle and rotator cuff tissue are structural components that maintain the dynamic stability of the shoulder joint. However, atrophy of the deltoid muscle may affect the stability of the shoulder joint, which in turn alters the mechanical distribution of rotator cuff tissue. Currently, the effect of muscle volume changes in the deltoid muscle on reducing the load on the rotator cuff tissue is still unknown. Therefore, this paper intends to analyze the mechanical changes of rotator cuff tissue by deltoid muscle atrophy through finite elements. Based on previously published finite element shoulder models, the deltoid muscle was modeled by constructing deltoid muscle models with different degrees of atrophy as, 100% deltoid muscle (Group 1), 80% deltoid muscle (Group 2), and 50% deltoid muscle (Group 3), respectively. The three models were given the same external load to simulate glenohumeral joint abduction, and the stress changes in the rotator cuff tissue were analyzed and recorded. In all three models, the stress in the rotator cuff tissue showed different degrees of increase with the increase of abduction angle, especially in the supraspinatus muscle. At 90° of glenohumeral abduction, supraspinatus stress increased by 58% and 118% in Group 2 and Group 3, respectively, compared with Group 1; In the subscapularis, the stress in Group 3 increased by 59% and 25% compared with Group 1 and Group 2, respectively. In addition, the stress of the infraspinatus muscle and teres minor muscle in Group 2 and Group 3 were higher than that in Group 1 during the abduction angle from 30° to 90°. Deltoid atrophy alters the abduction movement pattern of the glenohumeral joint. During glenohumeral abduction activity, deltoid atrophy significantly increases the stress on the rotator cuff tissue, whereas normal deltoid volume helps maintain the mechanical balance of the rotator cuff tissue.

Exercise Attenuate Diaphragm Atrophy in COPD Mice via Inhibiting the RhoA/ROCK Signaling.

Background: Exercise is an indispensable component of pulmonary rehabilitation with strong anti-inflammatory effects. However, the mechanisms by which exercise prevents diaphragmatic atrophy in COPD (chronic obstructive pulmonary disease) remain unclear. Methods: Forty male C57BL/6 mice were assigned to the control (n=16) and smoke (n=24) groups. Mice in the smoke group were exposed to the cigarette smoke (CS) for six months. They were then divided into model and exercise training groups for 2 months. Histological changes were observed in lung and diaphragms. Subsequently, agonist U46639 and antagonist Y27632 of RhoA/ROCK were subjected to mechanical stretching in LPS-treated C2C12 myoblasts. The expression levels of Atrogin-1, MuRF-1, MyoD, Myf5, IL-1ß, TNF-α, and RhoA/ROCK were determined by Western blotting. Results: Diaphragmatic atrophy and increased RhoA/ROCK expression were observed in COPD mice. Exercise training attenuated diaphragmatic atrophy, decreased the expression of MuRF-1, and increased MyoD expression in COPD diaphragms. Exercise also affects the upregulation of RhoA/ROCK and inflammation-related proteins. In in vitro experiments with C2C12 myoblasts, LPS remarkably increased the level of inflammation and protein degradation, whereas Y27632 or combined with mechanical stretching prevented this phenomenon considerably. Conclusion: RhoA/ROCK plays an important role in the prevention of diaphragmatic atrophy in COPD.

Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS.

Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.

Muscle weakness and mitochondrial stress occur before severe metastasis in a novel mouse model of ovarian cancer cachexia.

OBJECTIVES: A high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice. METHODS: Here, we evaluated a new model of ovarian cancer-induced cachexia with the advantages of inducing cancer in adult immunocompetent C57BL/6J mice through orthotopic injections of EOC cells in the ovarian bursa. We characterized the development of metastasis, ascites, muscle atrophy, muscle weakness, markers of inflammation, and mitochondrial stress in the tibialis anterior (TA) and diaphragm ∼45, ∼75 and ∼90 days after EOC injection. RESULTS: Primary ovarian tumour sizes were progressively larger at each time point while severe metastasis, ascites development, and reductions in body, fat and muscle weights occurred by 90 Days. There were no changes in certain inflammatory (TNFα), atrogene (MURF1 and Atrogin) or GDF15 markers within both muscles whereas IL-6 was increased at 45 and 90 Day groups in the diaphragm. TA weakness in 45 Day preceded atrophy and metastasis that were observed later (75 and 90 Day, respectively). The diaphragm demonstrated both weakness and atrophy in 45 Day. In both muscles, this pre-severe-metastatic muscle weakness corresponded with considerable reprogramming of gene pathways related to mitochondrial bioenergetics as well as reduced functional measures of mitochondrial pyruvate oxidation and creatine-dependent ADP/ATP cycling as well as increased reactive oxygen species emission (hydrogen peroxide). Remarkably, muscle force per unit mass at 90 days was partially restored in the TA despite the presence of atrophy and severe metastasis. In contrast, the diaphragm demonstrated progressive weakness. At this advanced stage, mitochondrial pyruvate oxidation in both muscles exceeded control mice suggesting an apparent metabolic super-compensation corresponding with restored indices of creatine-dependent adenylate cycling. CONCLUSIONS: This mouse model demonstrates the concurrent development of cachexia and metastasis that occurs in women with EOC. The model provides physiologically relevant advantages of inducing tumour development within the ovarian bursa in immunocompetent adult mice. Moreover, the model reveals that muscle weakness in both TA and diaphragm precedes severe metastasis while weakness also precedes atrophy in the TA. An underlying mitochondrial bioenergetic stress corresponded with this early weakness. Collectively, these discoveries can direct new research towards the development of therapies that target pre-atrophy and pre-severe-metastatic weakness during EOC in addition to therapies targeting cachexia.

Inflammatory Cytokine-Induced Muscle Atrophy and Weakness Can Be Ameliorated by an Inhibition of TGF-ß-Activated Kinase-1.

Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-ß-activated kinase-1 (TAK1) activation, inflammatory cytokine-induced muscle wasting may be ameliorated by the inhibition of TAK1 activity. The present study was undertaken to clarify whether TAK1 inhibition can ameliorate inflammation-induced muscle wasting. SKG/Jcl mice as an autoimmune arthritis animal model were treated with a small amount of mannan as an adjuvant to enhance the production of TNF-α and IL-1ß. The increase in these inflammatory cytokines caused a reduction in muscle mass and strength along with an induction of arthritis in SKG/Jcl mice. Those changes in muscle fibers were mediated via the phosphorylation of TAK1, which activated the downstream signaling cascade via NF-κB, p38 MAPK, and ERK pathways, resulting in an increase in myostatin expression. Myostatin then reduced the expression of muscle proteins not only via a reduction in MyoD1 expression but also via an enhancement of Atrogin-1 and Murf1 expression. TAK1 inhibitor, LL-Z1640-2, prevented all the cytokine-induced changes in muscle wasting. Thus, TAK1 inhibition can be a new therapeutic target of not only joint destruction but also muscle wasting induced by inflammatory cytokines.

Characterization of Undiscovered miRNA Involved in Tumor Necrosis Factor Alpha-Induced Atrophy in Mouse Skeletal Muscle Cell Line.

Muscular atrophy is a complex catabolic condition that develops due to several inflammatory-related disorders, resulting in muscle loss. Tumor necrosis factor alpha (TNF-α) is believed to be one of the leading factors that drive inflammatory response and its progression. Until now, the link between inflammation and muscle wasting has been thoroughly investigated, and the non-coding RNA machinery is a potential connection between the candidates. This study aimed to identify specific miRNAs for muscular atrophy induced by TNF-α in the C2C12 murine myotube model. The difference in expression of fourteen known miRNAs and two newly identified miRNAs was recorded by next-generation sequencing between normal muscle cells and treated myotubes. After validation, we confirmed the difference in the expression of one novel murine miRNA (nov-mmu-miRNA-1) under different TNF-α-inducing conditions. Functional bioinformatic analyses of nov-mmu-miRNA-1 revealed the potential association with inflammation and muscle atrophy. Our results suggest that nov-mmu-miRNA-1 may trigger inflammation and muscle wasting by the downregulation of LIN28A/B, an anti-inflammatory factor in the let-7 family. Therefore, TNF-α is involved in muscle atrophy through the modulation of the miRNA cellular machinery. Here, we describe for the first time and propose a mechanism for the newly discovered miRNA, nov-mmu-miRNA-1, which may regulate inflammation and promote muscle atrophy.

Myogenic microRNAs as Therapeutic Targets for Skeletal Muscle Mass Wasting in Breast Cancer Models.

Breast cancer is the type of cancer with the highest prevalence in women worldwide. Skeletal muscle atrophy is an important prognostic factor in women diagnosed with breast cancer. This atrophy stems from disrupted skeletal muscle homeostasis, triggered by diminished anabolic signalling and heightened inflammatory conditions, culminating in an upregulation of skeletal muscle proteolysis gene expression. The importance of delving into research on modulators of skeletal muscle atrophy, such as microRNAs (miRNAs), which play a crucial role in regulating cellular signalling pathways involved in skeletal muscle protein synthesis and degradation, has been recognised. This holds true for conditions of homeostasis as well as pathologies like cancer. However, the determination of specific miRNAs that modulate skeletal muscle atrophy in breast cancer conditions has not yet been explored. In this narrative review, we aim to identify miRNAs that could directly or indirectly influence skeletal muscle atrophy in breast cancer models to gain an updated perspective on potential therapeutic targets that could be modulated through resistance exercise training, aiming to mitigate the loss of skeletal muscle mass in breast cancer patients.

The Extract of Gloiopeltis tenax Enhances Myogenesis and Alleviates Dexamethasone-Induced Muscle Atrophy.

The decline in the function and mass of skeletal muscle during aging or other pathological conditions increases the incidence of aging-related secondary diseases, ultimately contributing to a decreased lifespan and quality of life. Much effort has been made to surmise the molecular mechanisms underlying muscle atrophy and develop tools for improving muscle function. Enhancing mitochondrial function is considered critical for increasing muscle function and health. This study is aimed at evaluating the effect of an aqueous extract of Gloiopeltis tenax (GTAE) on myogenesis and muscle atrophy caused by dexamethasone (DEX). The GTAE promoted myogenic differentiation, accompanied by an increase in peroxisome proliferator-activated receptor γ coactivator α (PGC-1α) expression and mitochondrial content in myoblast cell culture. In addition, the GTAE alleviated the DEX-mediated myotube atrophy that is attributable to the Akt-mediated inhibition of the Atrogin/MuRF1 pathway. Furthermore, an in vivo study using a DEX-induced muscle atrophy mouse model demonstrated the efficacy of GTAE in protecting muscles from atrophy and enhancing mitochondrial biogenesis and function, even under conditions of atrophy. Taken together, this study suggests that the GTAE shows propitious potential as a nutraceutical for enhancing muscle function and preventing muscle wasting.

Skeletal muscle immobilisation-induced atrophy: mechanistic insights from human studies.

Periods of skeletal muscle disuse lead to rapid declines in muscle mass (atrophy), which is fundamentally underpinned by an imbalance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB). The complex interplay of molecular mechanisms contributing to the altered regulation of muscle protein balance during disuse have been investigated but rarely synthesised in the context of humans. This narrative review discusses human models of muscle disuse and the ensuing inversely exponential rate of muscle atrophy. The molecular processes contributing to altered protein balance are explored, with a particular focus on growth and breakdown signalling pathways, mitochondrial adaptations and neuromuscular dysfunction. Finally, key research gaps within the disuse atrophy literature are highlighted providing future avenues to enhance our mechanistic understanding of human disuse atrophy.