Muscle Atrophy Research Articles

Lifelong dietary protein restriction induces denervation and skeletal muscle atrophy in mice

As a widespread global issue, protein deficiency hinders development and optimal growth in offspring. Maternal low-protein diet influences the development of age-related diseases, including sarcopenia, by altering the epigenome and organ structure through potential increase in oxidative stress. However, the long-term effects of lactational protein restriction or postnatal lifelong protein restriction on the neuromuscular system have yet to be elucidated. Our results demonstrated that feeding a normal protein diet after lactational protein restriction did not have significant impacts on the neuromuscular system in later life. In contrast, a lifelong low-protein diet induced a denervation phenotype and led to demyelination in the sciatic nerve, along with an increase in the number of centralised nuclei and in the gene expression of atrogenes at 18 months of age, indicating an induced skeletal muscle atrophy. These changes were accompanied by an increase in proteasome activity in skeletal muscle, with no significant alterations in oxidative stress or mitochondrial dynamics markers in skeletal muscle later in life. Thus, lifelong protein restriction may induce skeletal muscle atrophy through changes in peripheral nerves and neuromuscular junctions, potentially contributing to the early onset or exaggeration of sarcopenia.

Factors correlating with positive electrodiagnostic findings for neurogenic thoracic outlet syndrome

IntroductionDiagnosis of neurogenic thoracic outlet syndrome (nTOS) remains a challenge. The role of electrodiagnostic studies (EDX) in the workup of nTOS remains controversial. The aim of this study was to report EDX findings in a cohort of patients undergoing surgery for nTOS and also analyse patient related and intraoperative factors associated with positive EDX findings supportive of a diagnosis of NTOS. MethodsBaseline characteristics of patients including age, sex, duration of symptoms, type of nTOS, and pattern of brachial plexus involvement were gathered and analysed. All patients received a preoperative EDX evaluation and were divided into two groups based on positive or negative EDX results for comparison. ResultsA total of 30 consecutive patients were included in this study comprising 11 (36.7%) male and 19 (63.3%) female patients, with a mean age of 44.6 ± 17.6 years. When classified by type of nTOS, 22 (73.3%) patients had type 1 nTOS with muscle weakness and atrophy, followed by 7 (23.4%) patients with type 3, and one (3.3%) patient with type 2 nTOS. In terms of the pattern of nTOS, 26 (86.7%) patients had lower plexus pattern of involvement (C8-T1), followed by 17 (56.7%) with upper-middle plexus pattern (C6-C7), and 13 (43.3%) with upper plexus pattern (C5-dorsal scapular nerve (DSN)). When comparing the characteristics of patients with positive and negative EDX findings suggestive of nTOS, only older age and type 1 nTOS (P<0.05) were significantly associated with positive EDX findings. ConclusionsEDX assessment, at this point in time, may not be the best modality for diagnosis of nTOS. Interindividual variation in findings reported by different clinicians performing the EDX remains a significant limiting factor. Older patients and those with more severe nTOS (type 1) are more likely to have positive results with EDX.

Diaphragm Muscle Atrophy Contributes to Low Physical Capacity in COVID-19 Survivors.

Fatigue and dyspnea are the most commonly reported long-term complaints in individuals previously infected with SARS-CoV-2. This study aimed to comprehensively evaluate diaphragm muscle function in post-COVID-19 patients and investigate whether potential diaphragm dysfunction contributes to physical functioning impairment. A total of 46 patients who qualified for pulmonary rehabilitation were examined. Diaphragm muscle function parameters were evaluated using ultrasonography, while the severity of dyspnea, aerobic capacity, and the amount of energy used by the body during physical activity were assessed using the six-minute walk test, mMRC scale, and Metabolic Equivalent Task (MET), respectively. We identified that 69.5% of patients had diaphragm atrophy and 6.5% had diaphragm paralysis. The percentage of atrophy was not related to age, gender, BMI, oxygen therapy usage during the COVID-19 infection course, and disease severity. Patients who experienced cough, fever, and no loss of smell during the COVID-19 course had significantly greater diaphragm inspiratory thickness values, while patients with cough and no smell disorders had a significantly lower percentage of diaphragm atrophy. Diaphragm functional parameters were strongly associated with selected variables of exercise tolerance, such as distance in the six-minute walk test, oxygen saturation levels, fatigue, and exertion on the Borg scale. In conclusion, diaphragm muscle dysfunction is a serious long-term post-COVID-19 consequence and can be viewed as a major contributing factor to prolonged functional impairments.

Quantification of muscle recovery in post-ICU patients admitted for acute pancreatitis: a longitudinal single-center study

ObjectivesCritically ill patients with severe pancreatitis exhibit substantial muscle wasting, which limits in-hospital and post-hospital outcomes. Survivors of critical illness undergo extensive recovery processes. Previous studies have explored pancreatic function, quality of life, and costs post-hospitalization for AP patients, but none have comprehensively quantified muscle loss and recovery post-discharge. By applying an AI-based automated segmentation tool, we aimed to quantify muscle mass recovery in ICU patients after discharge.MaterialsMuscle segmentation was performed on 22 patients, with a minimum of three measurements taken during hospitalization and one clinically indicated examination after hospital discharge. Changes in psoas muscle area (PMA) between admission, discharge and follow up were calculated. T-Test was performed to identify significant differences between patients able and not able to recover their muscle mass.ResultsMonitoring PMA shows muscle loss during and gain after hospitalization: The mean PMA at the first scan before or at ICU admission (TP1) was 17.08 cm², at the last scan before discharge (TP2), mean PMA was 9.61 cm². The percentage change in PMA between TP1 and TP2 ranged from − 85.42% to -2.89%, with a mean change of -40.18%. The maximum muscle decay observed during the stay was − 50.61%. After a mean follow-up period of 438.73 days most patients (81%) were able to increase their muscle mass. Compared to muscle status at TP1, only 27% of patients exhibited full recovery, with the majority still presenting a deficit of 31.96%.ConclusionMuscle recovery in ICU patients suffering from severe AP is highly variable, with only about one third of patients recovering to their initial physical status. Opportunistic screening of post-ICU patient recovery using clinically indicated imaging and AI-based segmentation tools enables precise quantification of patients’ muscle status and can be employed to identify individuals who fail to recover and would benefit from secondary rehabilitation. Understanding the dynamics of muscle atrophy may improve prognosis and support personalized patient care.

Glucocorticoid treatment increases cholesterol availability during critical illness: effect on adrenal and muscle function

BackgroundHypocholesterolemia hallmarks critical illness though the underlying pathophysiology is incompletely understood. As low circulating cholesterol levels could partly be due to an increased conversion to cortisol/corticosterone, we hypothesized that glucocorticoid treatment, via reduced de novo adrenal cortisol/corticosterone synthesis, might improve cholesterol availability and as such affect adrenal gland and skeletal muscle function.MethodsIn a matched set of prolonged critically ill patients (n = 324) included in the EPaNIC RCT, a secondary analysis was performed to assess the association between glucocorticoid treatment and plasma cholesterol from ICU admission to day five. Next, in a mouse model of cecal ligation and puncture-induced sepsis, septic mice were randomized to receive either hydrocortisone (1.2 mg/day) (n = 17) or placebo (n = 15) for 5 days, as compared with healthy mice (n = 18). Plasma corticosterone, cholesterol, and adrenocortical and myofiber cholesterol were quantified. Adrenal structure and steroidogenic capacity were evaluated. Muscle force and markers of atrophy, fibrosis and regeneration were quantified. In a consecutive mouse study with identical design (n = 24), whole body composition was assessed by EchoMRI to investigate impact on lean mass, fat mass, total and free water.ResultsIn human patients, glucocorticoid treatment was associated with higher plasma HDL- and LDL-cholesterol from respectively ICU day two and day three, up to day five (P < 0.05). Plasma corticosterone was no longer elevated in hydrocortisone-treated septic mice compared to placebo, whereas the sepsis-induced reduction in plasma HDL- and LDL-cholesterol and in adrenocortical cholesterol was attenuated (P < 0.05), but without improving the adrenocortical ACTH-induced CORT response and with increased adrenocortical inflammation and apoptosis (P < 0.05). Total body mass was further decreased in hydrocortisone-treated septic mice (P < 0.01) compared to placebo, with no additional effect on muscle mass, force or myofiber size. The sepsis-induced rise in markers of muscle atrophy and fibrosis was unaffected by hydrocortisone treatment, whereas markers of muscle regeneration were suppressed compared to placebo (P < 0.05). An increased loss of lean body mass and total and free water was observed in hydrocortisone-treated septic mice compared to placebo (P < 0.05).ConclusionsGlucocorticoid treatment partially attenuated critical illness-induced hypocholesterolemia, but at a cost of impaired adrenal function, suppressed muscle regeneration and exacerbated loss of body mass.Graphical abstract

Resveratrol as a potential therapeutic agent for sarcopenic obesity: Insights from in vivoperiments

Sarcopenic obesity (SO) is a metabolic disorder with increasing prevalence. It is characterized by a reduction in skeletal muscle mass and strength. Resveratrol (RSV) is one of the most frequently used herbs in the treatment of skeletal muscle atrophy. However, the precise mechanism of the action of RSV in SO remains unclear. The objective of this study was to examine the pharmacological mechanism of RSV in the context of SO through the lens of network pharmacology, to validate these findings through in vivo experimentation. A list of potential RSV targets was compiled by retrieving the data from multiple databases. This list was then cross-referenced with a list of potential targets related to SO. The intersections of RSV- and SO-related targets were analyzed using Venn diagrams. To identify the core genes, a protein-protein interaction (PPI) network of the intersection targets was constructed and subsequently analyzed. Molecular docking was used to predict RSV binding to its core targets. A high-fat diet was used to induce SO in mice. These findings indicated that RSV may prevent SO by acting on 11 targets. Among these, interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor (TNF) are considered core targets. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results indicated that the anti-SO effect of RSV was predominantly linked to metabolic disease-related pathways, including those associated with nonalcoholic fatty liver disease. The anti-inflammatory effects of RSV were confirmed in vivo in an SO mouse model. This study contributes to a more comprehensive understanding of the key mechanisms of the action of RSV against SO and provides new possibilities for drug development in the pathological process of SO.

GSDMD KNOCKOUT ALLEVIATES SEPSIS-ASSOCIATED SKELETAL MUSCLE ATROPHY BY INHIBITING IL18/AMPK SIGNALING.

Background: Sepsis commonly leads to skeletal muscle atrophy, characterized by substantial muscle weakness and degeneration, ultimately contributing to an adverse prognosis. Studies have shown that programmed cell death is an important factor in the progression of muscle loss in sepsis. However, the precise role and mechanism of pyroptosis in skeletal muscle atrophy are not yet fully comprehended. Therefore, we aimed to examine the role and mechanism of action of the pyroptosis effector protein GSDMD in recognized cellular and mouse models of sepsis. Methods: The levels of GSDMD and N-GSDMD in skeletal muscle were evaluated 2, 4, and 8 days after cecal ligation and puncture. Sepsis was produced in mice that lacked the Gsdmd gene (Gsdmd knockout) and in mice with the normal Gsdmd gene (wild-type) using a procedure called cecal ligation and puncture. The degree of muscular atrophy in the gastrocnemius and tibialis anterior muscles was assessed 72 h after surgery in the septic mouse model. In addition, the architecture of skeletal muscles, protein expression, and markers associated with pathways leading to muscle atrophy were examined in mice from various groups 72 h after surgery. The in vitro investigations entailed the use of siRNA to suppress Gsdmd expression in C2C12 cells, followed by stimulation of these cells with lipopolysaccharide to evaluate the impact of Gsdmd downregulation on muscle atrophy and the related signaling cascades. Results: This study has demonstrated that the GSDMD protein, known as the "executive" protein of pyroptosis, plays a crucial role in the advancement of skeletal muscle atrophy in septic mice. The expression of N-GSDMD in the skeletal muscle of septic mice was markedly higher compared with the control group. The Gsdmd knockout mice exhibited notable enhancements in survival, muscle strength, and body weight compared with the septic mice. Deletion of the Gsdmd gene reduced muscular wasting in the gastrocnemius and tibialis anterior muscles caused by sepsis. Studies conducted in living organisms ( in vivo ) and in laboratory conditions ( in vitro ) have shown that the absence of the Gsdmd gene decreases indicators of muscle loss associated with sepsis by blocking the IL18/AMPK signaling pathway. Conclusion: The results of this study demonstrate that the lack of Gsdmd has a beneficial effect on septic skeletal muscle atrophy by reducing the activation of IL18/AMPK and inhibiting the ubiquitin-proteasome system and autophagy pathways. Therefore, our research provides vital insights into the role of pyroptosis in sepsis-related skeletal muscle wasting, which could potentially lead to the development of therapeutic and interventional approaches for preventing septic skeletal muscle atrophy.

Sequencing technology in sarcopenia: current research progress and future trends.

Muscle is an important tissue of the human body. Muscle atrophy is common in people of all ages, which will lead to human weakness and decline of motor function, which is one of the important causes of disability. The common methods of genomics research are transcriptome, proteomics and metabolomics, which are important means to explore the molecular pathology of diseases. In recent years, combinatorial research has been carried out on a large scale in the field of muscle atrophy. However, no author in this field has carried out bibliometrics and visual analysis. In this study, articles related to the histological study of muscular dystrophy since 2000 were searched from the Web of Science core database (WoSCC). We will retrieve the results through CiteSpace, VosViewer and R for data statistics and visual analysis. In this study, a total of 141 publications were collected, and the number of publications increased year by year. These 141 articles came from 1031 co-authors from 361 institutions in 31 countries and were published in 92 journals. A total of 6286 articles from 1383 journals were cited. Authors from American institutions have published the most articles and have been cited the most, and authors from other countries have also made considerable contributions. This is the first bibliometric and visual analysis of published research in the field of muscular dystrophy through systematic data retrieval and combined with a variety of bibliometric analysis tools. Through these data, we summarize the previous studies of scholars, and provide prospects for future research in the field.

Analysis of combinatory effects of free weight resistance training and a high-protein diet on body composition and strength capacity in postmenopausal women - A 12-week randomized controlled trial

BackgroundMenopause has a significant impact on the endocrine system of middle-aged women, resulting in a loss of skeletal muscle mass (SMM), changes in fat mass (FM) and a reduction in strength capacity. Resistance training (RT) and a high-protein diet (HPD) are effective methods for maintaining or increasing SMM. This study aims to determine the effects of HPD and RT on body composition, muscle thickness and strength capacity in postmenopausal women. MethodsIn total 55 healthy postmenopausal women (age: 58.2 ± 5.6 years, weight 69.1 ± 9.6 kg, height 166.5 ± 6.5 cm) successfully participated in the study. The women were randomly assigned to either group: training + protein (2.5 g/kg fat-free mass (FFM)) (n = 15; TP); only training (n = 12; T); only protein (2.5 g/kg FFM) (n = 14; CP) or control (n = 14; C). TP and T performed RT for 12 weeks with three training sessions and five exercises each. CP and C were prohibited from training during the period. The main parameters analysed for body composition were FFM, SMM, FM, muscle thickness of the M. rectus femoris, M. biceps femoris, M. triceps brachii and M. biceps brachii muscles. Strength was tested using a dynamometer for grip strength and 1-RM in the squat (BBS) and deadlift (DL). ResultsThe SMM significantly increased by RT (TP: (Δ+1.4 ± 0.9 kg; p < 0.05; d = 0.4; T: Δ+1.2 ± 1.3kg; p < 0.05; d = 0.3) and FM could be reduced only in T: (Δ−2.4 ± 2.9 kg; p < 0.05; d = 0.3). In muscle thickness a significant increase in the M. biceps brachii in both training groups (TP: (Δ+0.4 ± 0.3 cm; p < 0.05; d = 1.6; T: (Δ+0.3 ± 0.3 cm; p < 0.05; d = 0.9) and in M. biceps femoris only in TP (Δ+0.3 ± 0.4 cm; p < 0.05; d = 0.9) were observed. HPD without training does not affect body composition, A significant increase in grip strength (TP: Δ+4.7 ± 2.4 kg; (p < 0.05; d = 1.5; T: (Δ+3.6 ± 3.0 kg; p < 0.05; d = 0.8), in BBS (TP: (Δ+30.0 ± 14.2 kg; p < 0.05; d = 1.5; T: (Δ+34.0 ± 12.0 kg; p < 0.05; d = 2.4) and in DL (TP: (Δ+20.8 ± 10.3 kg; p < 0.05; d = 1.6; T: (Δ+22.1 ± 7.6 kg; p < 0.05; d = 2.0) was observed in both training groups. The CP also recorded a significant increase in the BBS (Δ+7.5 ± 5.4 kg; p < 0.05; d = 0.4) and in DL (Δ+5.5 ± 7.7 kg; p < 0.05; d = 0.5). No significant differences were detected for TP and T for any of the parameters. ConclusionThe results indicate that RT enhances body composition and strength capacity in postmenopausal women and is a preventive strategy against muscle atrophy. Besides HPD without training has a trivial significant effect on BBS and DL. HPD with RT has no clear additive effect on body composition and strength capacity. Further studies are needed to confirm these observations.

Long-term effects of the chronic administration of doxorubicin on aged skeletal muscle: An exploratory study in mice

The widely used chemotherapeutic drug doxorubicin (DOX) has been associated with adverse effects on the skeletal muscle, which can persist for years after the end of the treatment. These adverse effects may be exacerbated in older patients, whose skeletal muscle might already be impaired by aging. Nonetheless, the mediators responsible for DOX-induced myotoxicity are still largely unidentified, particularly the ones involved in the long-term effects that negatively affect the quality of life of the patients. Therefore, this study aimed to investigate the long-term effects of the chronic administration of DOX on the soleus muscle of aged mice. For that and to mimic the clinical regimen, a dose of 1.5 mg kg−1 of DOX was administered two times per week for three consecutive weeks in a cumulative dose of 9 mg kg−1 to 19-month-old male mice, which were sacrificed two months after the last administration. Body wasting and the atrophy of the soleus muscle, as measured by a decrease in the cross-sectional area of the soleus muscle fibers, were identified as long-term effects of DOX administration. The atrophy observed was correlated with increased reactive oxygen species production and caspase-3 activity. An impaired skeletal muscle regeneration was also suggested due to the correlation between satellite cells activation and the soleus muscle fibers atrophy. Systemic inflammation, skeletal muscle energy metabolism and neuromuscular junction-related markers do not appear to be involved in the long-term DOX-induced skeletal muscle atrophy. The data provided by this study shed light on the mediators involved in the overlooked long-term DOX-induced myotoxicity, paving the way to the improvement of the quality of life and survival rates of older cancer patients.

Muscle-enriched microRNA-486-mediated regulation of muscular atrophy and exercise.

The objectives of this review were to understand the impact of microRNA-486 on myogenesis and muscle atrophy, and the change of microRNA-486 following exercise, and provide valuable information for improving muscle atrophy based on exercise intervention targeting microRNA-486. Muscle-enriched microRNAs (miRNAs), also referred to as myomiRs, control various processes in skeletal muscles, from myogenesis and muscle homeostasis to different responses to environmental stimuli such as exercise. MicroRNA-486 is a miRNA in which a stem-loop sequence is embedded within the ANKYRIN1 (ANK1) locus and is strictly conserved across mammals. MicroRNA-486 is involved in the development of muscle atrophy caused by aging, immobility, prolonged exposure to microgravity, or muscular and neuromuscular disorders. PI3K/AKT signaling is a positive pathway, as it increases muscle mass by increasing protein synthesis and decreasing protein degradation. MicroRNA-486 can activate this pathway by inhibiting phosphatase and tensin homolog (PTEN), it may also indirectly inhibit the HIPPO signaling pathway to promote cell growth. Exercises regulate microRNA-486 expression both in blood and muscle. This review focused on the recent elucidation of sarcopenia regulation by microRNA-486 and its effects on pathological states, including primary muscular disease, secondary muscular disorders, and age-related sarcopenia. Additionally, the role of exercise in regulating skeletal muscle-enriched microRNA-486 was highlighted, along with its physiological significance. Growing evidence indicates that microRNA-486 significantly impacts the development of muscle atrophy. MicroRNA-486 has great potential to become a therapeutic target for improving muscle atrophy through exercise intervention.

17β-Trenbolone Exposure Enhances Muscle Activity and Exacerbates Parkinson's Disease Progression in Male Mice.

Parkinson's disease (PD) ranks as the second most prevalent neurodegenerative disorder, and while the neuroprotective effects of estrogen are well-documented, the impact of androgens on neurological disorders remains understudied. The consequences of exposure to 17-trenbolone (17-TB), an environmental endocrine disruptor with androgen-like properties, on the mammalian nervous system have received limited attention. Therefore, in this study, we aimed to investigate the biological effects of 17-TB exposure on PD. In our investigation using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, we discovered that 17-TB exposure elevated testosterone hormone levels prevented androgen receptor (AR) reduction, upregulated the expression of muscular dystrophic factors (Atrogin1, MuRF1, Musa1, and Myostatin), improved muscle strength, and enhanced locomotor activity in the open field test. However, it is noteworthy that exposure to 17-TB also led to an upregulation of neuroinflammatory cytokines (NLRP3, IL-6, IL-1α, and IL-1β) in PD mice. Crucially, 17-TB exposure induced downregulation of nigral apoptotic proteins DJ-1 and Bcl-2 while upregulating Bax and Caspase-3 in PD mice. This exacerbated neuronal apoptosis, ultimately intensifying dopaminergic neuronal degeneration and death in the substantia nigra and striatum of PD mice. In conclusion, our findings indicate that while 17-TB mitigates muscle atrophy and enhances motor activity in PD mice, it concurrently exacerbates neuroinflammation, induces neuronal apoptosis, and worsens dopaminergic neuronal death, thereby aggravating the progression of MPTP-induced Parkinsonism. This underscores the importance of considering potential environmental risks in neurodegeneration associated with Parkinson's disease, providing a cautionary tale for our daily exposure to environmental endocrine chemical disruptors.

Unacylated Ghrelin Protects Against Age-Related Loss of Muscle Mass and Contractile Dysfunction in Skeletal Muscle.

Sarcopenia, the progressive loss of muscle mass and function, universally affects older adults and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut-released hormone that increases appetite and body weight through acylation. Acylated ghrelin activates its receptor, growth hormone secretagogue receptor 1a (GHSR1a), in the brain by binding to it. Studies have demonstrated that acyl and unacylated ghrelin (UnAG) both have protective effects against acute pathological conditions independent of receptor activation. Here, we investigated the long-term effects of UnAG in age-associated muscle atrophy and contractile dysfunction in mice. Four-month-old and 18-month-old mice were subjected to either UnAG or control treatment for 10 months. UnAG did not affect food consumption or body weight. Gastrocnemius and quadriceps muscle weights were reduced by 20%-30% with age, which was partially protected against by UnAG. Specific force, force per cross-sectional area, measured in isolated extensor digitorum longus muscle was diminished by 30% in old mice; however, UnAG prevented the loss of specific force. UnAG also protected from decreases in mitochondrial respiration and increases in hydrogen peroxide generation of skeletal muscle of old mice. Results of bulk mRNA-seq analysis and our contractile function data show that UnAG reversed neuromuscular junction impairment that occurs with age. Collectively, our data revealed the direct role of UnAG in mitigating sarcopenia in mice, independent of food consumption or body weight, implicating UnAG treatment as a potential therapy against sarcopenia.

Inhibition of MAT2A Impairs Skeletal Muscle Repair Function.

The regenerative capacity of muscle, which primarily relies on anabolic processes, diminishes with age, thereby reducing the effectiveness of therapeutic interventions aimed at treating age-related muscle atrophy. In this study, we observed a decline in the expression of methionine adenosine transferase 2A (MAT2A), which synthesizes S-adenosylmethionine (SAM), in the muscle tissues of both aged humans and mice. Considering MAT2A's critical role in anabolism, we hypothesized that its reduced expression contributes to the impaired regenerative capacity of aging skeletal muscle. Mimicking this age-related reduction in the MAT2A level, either by reducing gene expression or inhibiting enzymatic activity, led to inhibiting their differentiation into myotubes. In vivo, inhibiting MAT2A activity aggravated BaCl2-induced skeletal muscle damage and decreased the number of satellite cells, whereas supplementation with SAM improved these effects. RNA-sequencing analysis further revealed that the Fas cell surface death receptor (Fas) gene was upregulated in Mat2a-knockdown C2C12 cells. Suppressing MAT2A expression or activity elevated Fas protein levels and increased the proportion of apoptotic cells. Additionally, inhibition of MAT2A expression or activity increased p53 expression. In conclusion, our findings demonstrated that impaired MAT2A expression or activity compromised the regeneration and repair capabilities of skeletal muscle, partially through p53-Fas-mediated apoptosis.

Melatonin Regulates Rheumatoid Synovial Fibroblasts-Related Inflammation: Implications for Pathological Skeletal Muscle Treatment.

Melatonin has been reported to regulate circadian rhythms and have anti-inflammatory characteristics in various inflammatory autoimmune diseases, but its effects in diseases-associated muscle atrophy remain controversial. This study is aimed to determine the evidence of melatonin in rheumatoid arthritis (RA)-related pathological muscle atrophy. We used initially bioinformatics results to show that melatonin regulated significantly the correlation between pro-inflammation and myogenesis in RA synovial fibroblasts (RASF) and myoblasts. The conditioned medium (CM) from melatonin-treated RASF was incubated in myoblasts with growth medium and differentiated medium to investigate the markers of pro-inflammation, atrophy, and myogenesis. We found that melatonin regulated RASF CM-induced pathological muscle pro-inflammation and atrophy in myoblasts and differentiated myocytes through NF-κB signaling pathways. We also showed for the first time that miR-30c-1-3p is negatively regulated by three inflammatory cytokines in human RASF, which is associated with murine-differentiated myocytes. Importantly, oral administration with melatonin in a collagen-induced arthritis (CIA) mouse model also significantly improved arthritic swelling, hind limb grip strength as well as pathological muscle atrophy. In conclusion, our study is the first to demonstrate not only the underlying mechanism whereby melatonin decreases pro-inflammation in RA-induced pathological muscle atrophy but also increases myogenesis in myoblasts and differentiated myocytes.

Preoperative rotator cuff fatty infiltration and muscle atrophy do not negatively influence outcomes following anatomic total shoulder arthroplasty

BackgroundAnatomic total shoulder arthroplasty (TSA) is an effective surgical option for the treatment of primary glenohumeral osteoarthritis (GHOA) with an intact rotator cuff. While an intact rotator cuff is essential to the success of TSA, little is known about how preoperative rotator cuff muscle quality may impact clinical outcomes. In this study, we sought to determine the effects of rotator cuff fatty infiltration (FI) and muscle atrophy (MA) on clinical outcomes following TSA. MethodsA retrospective review of a prospectively maintained, single-surgeon registry was used to identify patients undergoing TSA for GHOA between April 2015 and March 2020. Patients were included if they had preoperative magnetic resonance imaging available, an intact rotator cuff, and complete preoperative and minimum 2-year postoperative patient-reported outcome measures (PROMs) and active range of motion (ROM) measurements. Preoperative MA and FI of the rotator cuff were assessed on magnetic resonance imaging by measuring muscle cross-sectional area and using the Goutallier classification system, respectively. Pearson’s correlation was used to determine any relationship between MA and clinical outcomes. Univariate analysis was used to compare clinical outcomes of patients with moderate-to-severe FI to those with minimal-to-mild FI. ResultsThere were 163 shoulders from 154 patients with a mean age of 62.5 (standard deviation = 7.4) and a mean follow-up of 2.9 years (standard deviation 1.2) that met inclusion criteria. Rotator cuff muscle area was not correlated with any preoperative or postoperative ROM or PROMs (P > .05). However, the ratio of infraspinatus and teres minor (posterior cuff) to subscapularis muscle area was minimally negatively correlated with change in Single Assessment Numerical Evaluation (r = −0.171, P = .029) and change in internal rotation (r = −0.207, P = .008), although the clinical relevance is unclear. No significant differences in preoperative ROM or PROMs were found between patients with minimal-to-mild and moderate-to-severe FI (P > .05). ConclusionPreoperative rotator cuff muscle volume and FI do not impact clinical outcomes following TSA in patients with GHOA and intact rotator cuffs. TSA remains a viable surgical treatment for individuals with GHOA and an intact rotator cuff, provided the MA and FI are not so severe that a patient may be indicated for another type of treatment.

Hotspots and trends in satellite cell research in muscle regeneration: A bibliometric visualization and analysis from 2010 to 2023

BackgroundThe incidence of muscle atrophy or sports injuries is increasing with time and population aging, thereby attracting considerable attention to muscle generation research. Muscle satellite cells, which play an important role in this process, lack comprehensive literature regarding their use for muscle regeneration. Hence, this study aimed to analyze the hotspots and trends in satellite cell research from 2010 to 2023, providing a reference for muscle regeneration research. MethodsStudies on satellite cells’ role in muscle regeneration from 2010 to 2023 were retrieved from the Web of Science Core Collection. Using CiteSpace and VOSviewer, we analyzed annual publications, authors and co-citing authors, countries and institutions, journals and co-citing journals, co-citing references, and keywords. ResultsFrom 2010 to 2023, 1468 papers were retrieved, indicating an overall increasing trend in the number of annual publications related to satellite cells in muscle regeneration. The United States had the highest number of publications, while the Institut National de la Santé et de la Recherche Médicale was the institution with the most publications. Among journals, " PloS One" had the highest number of published papers, and "Cell" emerged as the most co-cited journal. A total of 7425 authors were involved, with Michael A. Rudnicki being the author with the highest number of publications and the most co-cited author. The most cited reference was "Satellite cells and the muscle stem cell niche." Among keywords, “satellite cells” was the most common, with "heterogeneity" having the highest centrality. Frontier themes included "Duchenne muscular dystrophy,” "skeletal muscle,” "in-vivo,” "muscle regeneration,” "mice," "muscle atrophy,” "muscle fibers,” "inflammation,” " mesenchymal stem cells,” and "satellite cell." ConclusionThis study presents the current status and trends in satellite cell research on muscle regeneration from 2010 to 2023 using bibliometric analyses, providing valuable insights into numerous future research directions.

EDA2R-NIK signaling in cancer cachexia.

Cachexia is a debilitating condition causing weight loss and skeletal muscle wasting that negatively influences treatment and survival of cancer patients. The objective of this review is to describe recent discoveries on the role of a novel signaling pathway involving ectodysplasin A2 receptor (EDA2R) and nuclear factor κB (NFκB)-inducing kinase (NIK) in muscle atrophy. Studies identified tumor-induced upregulation of EDA2R expression in muscle tissues in pre-clinical cachexia models and patients with various cancers. Activation of EDA2R by its ligand promoted atrophy in cultured myotubes and muscle tissue, which depended on NIK activity. The non-canonical NFκB pathway via NIK also stimulated muscle atrophy. Mice lacking EDA2R or NIK were protected from muscle loss due to tumors. Tumor-induced cytokine oncostatin M (OSM) upregulated EDA2R expression in muscles whereas OSM receptor-deficient mice were resistant to muscle wasting. Recent discoveries revealed a mechanism involving EDA2R-NIK signaling and OSM that drives cancer-associated muscle loss, opening up new directions for designing anti-cachexia treatments. The therapeutic potential of targeting this mechanism to prevent muscle loss should be further investigated. Future research should also explore broader implications of the EDA2R-NIK pathway in other muscle wasting diseases and overall muscle health.

Bacterioruberin extract from Haloarchaea Haloferax marinum: Component identification, antioxidant activity and anti-atrophy effect in LPS-treated C2C12 myotubes.

Carotenoids are natural pigments utilized as colourants and antioxidants across food, pharmaceutical and cosmetic industries. They exist in carbon chain lengths of C30, C40, C45 and C50, with C40 variants being the most common. Bacterioruberin (BR) and its derivatives are part of the less common C50 carotenoid group, synthesized primarily by halophilic archaea. This study analysed the compositional characteristics of BR extract (BRE) isolated from 'Haloferax marinum' MBLA0078, a halophilic archaeon isolated from seawater near Yeoungheungdo Island in the Republic of Korea, and investigated its antioxidant activity and protective effect on lipopolysaccharide (LPS)-induced C2C12 myotube atrophy. The main components of BRE included all-trans-BR, monoanhydrobacterioruberin, 2-isopentenyl-3,4-dehydrorhodopin and all-trans-bisanhydrobacterioruberin. BRE exhibited higher antioxidant activity and DNA nicking protection activity than other well-known C40 carotenoids, such as β-carotene, lycopene and astaxanthin. In C2C12 myotubes, LPS treatment led to a reduction in myotube diameter and number, as well as the hypertranscription of the muscle-specific ubiquitin ligase MAFbx and MuRF1. BRE mitigated these changes by activating the Akt/mTOR pathway. Furthermore, BRE abolished the elevated cellular reactive oxygen species levels and the inflammation response induced by LPS. This study demonstrated that 'Hfx. marinum' is an excellent source of natural microbial C50 carotenoids with strong antioxidant capacity and may offer potential protective effects against muscle atrophy.

Ginsenoside Rc prevents dexamethasone-induced muscle atrophy and enhances muscle strength and motor function

BackgroundA decline in muscle mass and function can impact the health, disease vulnerability, and mortality of older adults. Prolonged use of high doses of glucocorticoids, such as dexamethasone (DEX), can cause muscle wasting and reduced strength. Ginsenoside Rc (gRc) has been shown to protect muscles by activating the PGC-1α pathway and improving mitochondrial function. The effects of gRc on muscle atrophy and function in mice are not fully understood. Methods and resultsThe study discovered that gRc prevented the DEX-induced decrease in viability of C2C12 myoblasts and myotubes. Furthermore, gRc inhibited myotube degradation and the upregulation of muscle degradation proteins induced by DEX. Transcriptome analysis of myotubes showed that gRc enhances muscle generation processes while suppressing the TGF-β pathway and oxidative stress response. In mice, gRc effectively reversed the reductions in body weight, muscle mass, and muscle fibers caused by DEX. Furthermore, gRc significantly enhanced muscle strength and exercise capacity. Docking and transcriptome analyses indicated that gRc may act as a competitive inhibitor of DEX at the glucocorticoid receptor, potentially preventing muscle loss. ConclusionThe study suggests that gRc can prevent DEX-induced muscle wasting and weakness. Consequently, it may be a viable treatment option for sarcopenia and muscle-related disorders in various medical conditions.