Hypoxia treatment and resistance training alters microRNA profiling in rats skeletal muscle.

MicroRNAs (miRNAs) may play a crucial regulatory role in the process of muscle atrophy induced by high-altitude hypoxia and its amelioration through resistance training. However, research in this aspect is still lacking. Therefore, this study aimed to employ miRNA microarray analysis to investigate the expression profile of miRNAs in skeletal muscle from an animal model of hypoxia-induced muscle atrophy and resistance training aimed at mitigating muscle atrophy. The study utilized a simulated hypoxic environment (oxygen concentration at 11.2%) to induce muscle atrophy and established a rat model of resistance training using ladder climbing, with a total intervention period of 4 weeks. The miRNA expression profile revealed 9 differentially expressed miRNAs influenced by hypoxia (e.g., miR-341, miR-32-5p, miR-465-5p) and 14 differentially expressed miRNAs influenced by resistance training under hypoxic conditions (e.g., miR-338-5p, miR-203a-3p, miR-92b-3p) (∣log2(FC)∣ ≥ 1.5, p < 0.05). The differentially expressed miRNAs were found to target genes involved in muscle protein synthesis and degradation (such as Utrn, mdm2, eIF4E), biological processes (such as negative regulation of transcription from RNA polymerase II promoter, regulation of transcription, DNA-dependent), and signaling pathways (such as Wnt signaling pathway, MAPK signaling pathway, ubiquitin-mediated proteolysis, mTOR signaling pathway). This study provides a foundation for understanding and further exploring the molecular mechanisms underlying hypoxia-induced rats muscle atrophy and the mitigation of atrophy through resistance training.

Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity.

There is considerable heterogeneity in the cardiometabolic abnormalities associated with obesity. We evaluated multi-organ system metabolic function in 20 adults with metabolically healthy obesity (MHO; normal fasting glucose and triglycerides, oral glucose tolerance, intrahepatic triglyceride content, and whole-body insulin sensitivity), 20 adults with metabolically unhealthy obesity (MUO; prediabetes, hepatic steatosis, and whole-body insulin resistance), and 15 adults who were metabolically healthy lean. Compared with MUO, people with MHO had (1) altered skeletal muscle biology (decreased ceramide content and increased expression of genes involved in BCAA catabolism and mitochondrial structure/function); (2) altered adipose tissue biology (decreased expression of genes involved in inflammation and extracellular matrix remodeling and increased expression of genes involved in lipogenesis); (3) lower 24-h plasma glucose, insulin, non-esterified fatty acids, and triglycerides; (4) higher plasma adiponectin and lower plasma PAI-1 concentrations; and (5) decreased oxidative stress. These findings provide a framework of potential mechanisms responsible for MHO and the metabolic heterogeneity of obesity. This study was registered at ClinicalTrials.gov (NCT02706262).

Plasma levels of Neurofilament light chain correlate with handgrip strength and sarcopenia in patients with chronic obstructive pulmonary disease.

BACKGROUND: Age-associated muscle decline, termed sarcopenia, is a common systemic effect of chronic obstructive pulmonary disease (COPD). Circulating Neurofilament light chain (NfL) levels reflect neuronal degradation and may be relevant to sarcopenia phenotype. However, such an association in COPD patients remains elusive. METHODS: We investigated male, 60-76 years old controls (n = 50) and COPD patients (n = 139) for plasma NfL levels in relation to sarcopenia and physical capacity markers. We measured handgrip strength (HGS), body composition, and short physical performance battery (SPPB) to evaluate sarcopenia and physical capacity. RESULTS: COPD patients had higher plasma NfL and lower HGS and SPPB performance than controls. Plasma NfL levels demonstrated negative associations with HGS and gait speed in COPD patients (all p < 0.05). Further, NfL levels were negatively associated with total SPPB scores in controls and patients with advanced COPD (p < 0.05). Plasma NfL also demonstrated an acceptable accuracy in diagnosing sarcopenia in controls (AUC = 0.757, p < 0.05) and COPD (AUC = 0.806, p < 0.05) patients. CONCLUSION: Collectively, plasma NfL may be helpful in evaluating sarcopenia phenotype and physical capacity in geriatric patients with COPD.

Unravelling the origin of isoprene in the human body - a forty year odyssey.

In the breath research community's search for volatile organic compounds that can act as non-invasive biomarkers for various diseases, hundreds of endogenous volatiles have been discovered. Whilst these systemic chemicals result from normal and abnormal metabolic activities or pathological disorders, to date very few are of any use for the development of clinical breath tests that could be used for disease diagnosis or to monitor therapeutic treatments. The reasons for this lack of application are manifold and complex, and these complications either limit or ultimately inhibit the analytical application of endogenous volatiles for use in the medical sciences. One such complication is a lack of knowledge on the biological origins of the endogenous volatiles. A major exception to this is isoprene. Since 1984, i.e., for forty years, it has been generally accepted that the pathway to the production of human isoprene, and hence the origin of isoprene in exhaled breath, is through cholesterol biosynthesis via the mevalonate (MVA) pathway within the liver. However, various studies between 2001 and 2012 provide compelling evidence that human isoprene is produced in skeletal muscle tissue. A recent multi-omic investigation of genes and metabolites has revealed that this proposal is correct by showing that human isoprene predominantly results from muscular lipolytic cholesterol metabolism. Despite the overwhelming proof for a muscular pathway to isoprene production in the human body, breath research papers still reference the hepatic MVA pathway. The major aim of this perspective is review the evidence that leads to a correct interpretation for the origins of human isoprene, so that the major pathway to human isoprene production is understood and appropriately disseminated. This is important, because an accurate attribution to the endogenous origins of isoprene is needed if exhaled isoprene levels are to be correctly interpreted and for assessing isoprene as a clinical biomarker.

Imaging-based diagnosis of sarcopenia for transplant-free survival in primary sclerosing cholangitis.

BACKGROUND: Imaging-based assessment of sarcopenia is a well-validated prognostic tool for patients with chronic liver disease. However, little is known about its value in patients with primary sclerosing cholangitis (PSC). This cross-sectional study aimed to investigate the predictive value of the cross-sectional imaging-based skeletal muscle index (SMI) for transplant-free survival (TFS) in patients with PSC. METHODS: A total of 95 patients with PSC who underwent abdominal cross-sectional imaging between 2008 and 2022 were included in this retrospective study. SMI was measured at the third lumbar vertebra level (L3-SMI). The cut-off values to define sarcopenia were < 50 cm²/m² in male patients and < 39 cm²/m² in female patients. The primary outcome of this study was TFS, which was defined as survival without liver transplantation or death from any cause. RESULTS: Our study indicates that L3-SMI sarcopenia impairs TFS in patients with PSC (5-year TFS: 33.9% vs. 83.3%, p = 0.001, log-rank test). L3-SMI sarcopenia was independently associated with reduced TFS via multivariate Cox regression analysis (HR = 2.749; p = 0.028). Body mass index reduction > 10% at 12 months, which is used as MELD standard exception (SE) criterion in Eurotransplant (in Germany only until September 2023), was not significantly associated with TFS in the multivariate Cox regression analysis (HR = 1.417; p = 0.330). Substitution of BMI reduction with L3-SMI in the German SE criteria improved the predictive accuracy of TFS compared to the established SE criteria (multivariable Cox regression analysis: HR = 4.007, p < 0.001 vs. HR = 1.691, p = 0.141). CONCLUSION: Imaging-based diagnosis of sarcopenia via L3-SMI is associated with a low TFS in patients with PSC and may provide additional benefits as a prognostic factor in patient selection for liver transplantation.

Molecular Transducers of Physical Activity Consortium (MoTrPAC): Human Studies Design and Protocol.

Physical activity, including structured exercise, is associated with favorable health-related chronic disease outcomes. While there is evidence of various molecular pathways that affect these responses, a comprehensive molecular map of these molecular responses to exercise has not been developed. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is a multi-center study designed to isolate the effects of structured exercise training on the molecular mechanisms underlying the health benefits of exercise and physical activity. MoTrPAC contains both a pre-clinical and human component. The details of the human studies component of MoTrPAC that include the design and methods are presented here. The human studies contain both an adult and pediatric component. In the adult component, sedentary participants are randomized to 12 weeks of Control, Endurance Exercise Training, or Resistance Exercise Training with outcomes measures completed before and following the 12 weeks. The adult component also includes recruitment of highly active endurance trained or resistance trained participants who only complete measures once. A similar design is used for the pediatric component; however, only endurance exercise is examined. Phenotyping measures include weight, body composition, vital signs, cardiorespiratory fitness, muscular strength, physical activity and diet, and other questionnaires. Participants also complete an acute rest period (adults only) or exercise session (adults, pediatrics) with collection of biospecimens (blood only for pediatrics) to allow for examination of the molecular responses. The design and methods of MoTrPAC may inform other studies. Moreover, MoTrPAC will provide a repository of data that can be used broadly across the scientific community.

Skeletal muscle differentiation induces wide-ranging nucleosome repositioning in muscle gene promoters.

In a previous report, we demonstrated that Cbx1, PurB and Sp3 inhibited cardiac muscle differentiation by increasing nucleosome density around cardiac muscle gene promoters. Since cardiac and skeletal muscle express many of the same proteins, we asked if Cbx1, PurB and Sp3 similarly regulated skeletal muscle differentiation. In a C2C12 model of skeletal muscle differentiation, Cbx1 and PurB knockdown increased myotube formation. In contrast, Sp3 knockdown inhibited myotube formation, suggesting that Sp3 played opposing roles in cardiac muscle and skeletal muscle differentiation. Consistent with this finding, Sp3 knockdown also inhibited various muscle-specific genes. The Cbx1, PurB and Sp3 proteins are believed to influence gene-expression in part by altering nucleosome position. Importantly, we developed a statistical approach to determine if changes in nucleosome positioning were significant and applied it to understanding the architecture of muscle-specific genes. Through this novel statistical approach, we found that during myogenic differentiation, skeletal muscle-specific genes undergo a set of unique nucleosome changes which differ significantly from those shown in commonly expressed muscle genes. While Sp3 binding was associated with nucleosome loss, there appeared no correlation with the aforementioned nucleosome changes. In summary, we have identified a novel role for Sp3 in skeletal muscle differentiation and through the application of quantifiable MNase-seq have discovered unique fingerprints of nucleosome changes for various classes of muscle genes during myogenic differentiation.

Down-regulation of neuronal form of Nitric oxide synthase in the Nurse cell of Trichinella spiralis.

The free radical nitric oxide (NO) and Ca2+ are critical regulators of skeletal muscle exercise performance and fatigue. The major source of NO in skeletal muscle cells is the neuronal form of the enzyme Nitric oxide synthase (nNOS). One of the most peculiar characteristics of the Nurse cell of Trichinella spiralis (T. spiralis) is the complete loss of the contractile capabilities of its derivative striated muscle fiber. The aim of the present study was to clarify the expression of nNOS protein and mRNA in striated muscles during the muscle phase of T. spiralis infection in mice. Muscle tissue samples were collected from mice at days 0, 14, 24, and 35 post infection (d.p.i.). The expression of nNOS was investigated by immunohistochemistry, and the expression levels of mRNA of mouse Nitric oxide synthase 1 (Nos1) by real-time PCR. The presence of nNOS protein was still well observable in the disintegrated sarcoplasm at the early stage of infection. The cytoplasm of the developing and mature Nurse cell showed the absence of this protein. At least at the beginning of the Nurse cell development, Trichinella uses the same repairing process of skeletal muscle cell, induced after any trauma and this corroborates very well our results concerning the nNOS expression on day 14 p.i. At a later stage, however, we could suggest that the down-regulation of nNOS in the Nurse cell of T. spiralis either serves a protective function or is an outcome of the genetic identity of the Nurse cell.

Muscle weakness and mitochondrial stress occur before 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 robust 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-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 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. Conclusion: 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 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-metastatic weakness during EOC in addition to therapies targeting cachexia.

Identification of mulberry leaf flavonoids and evaluating their protective effects on H2O2-induced oxidative damage in equine skeletal muscle satellite cells.

Introduction: Horses are susceptible to oxidative stress during strenuous endurance exercise, leading to muscle fatigue and damage. Mulberry leaf flavonoids (MLFs) possess significant antioxidant properties. However, the antioxidant efficacy of MLFs can be influenced by the extraction process, and their impact on H2O2-induced oxidative stress in equine skeletal muscle satellite cells (ESMCs) remains unexplored. Methods: Our study employed three extraction methods to obtain MLFs: ultrasound-assisted extraction (CEP), purification with AB-8 macroporous resin (RP), and n-butanol extraction (NB-EP). We assessed the protective effects of these MLFs on H2O2-induced oxidative stress in ESMCs and analyzed the MLF components using metabolomics. Results: The results revealed that pre-treatment with MLFs dose-dependently protected ESMCs against H2O2-induced oxidative stress. The most effective concentrations were 0.8 mg/mL of CEP, 0.6 mg/mL of RP, and 0.6 mg/mL of NB-EP, significantly enhancing EMSC viability (p < 0.05). These optimized MLF concentrations promoted the GSH-Px, SOD and T-AOC activities (p < 0.05), while reducing MDA production (p < 0.05) in H2O2-induced ESMCs. Furthermore, these MLFs enhanced the gene expression, including Nrf2 and its downstream regulatory genes (TrxR1, GPX1, GPX3, SOD1, and SOD2) (p < 0.05). In terms of mitochondrial function, ESMCs pre-treated with MLFs exhibited higher basal respiration, spare respiratory capacity, maximal respiration, ATP-linked respiration compared to H2O2-induced ESMCs (p < 0.05). Additionally, MLFs enhanced cellular basal glycolysis, glycolytic reserve, and maximal glycolytic capacity (p < 0.05). Metabolomics analysis results revealed significant differences in mulberrin, kaempferol 3-O-glucoside [X-Mal], neohesperidin, dihydrokaempferol, and isobavachalcone among the three extraction processes (p < 0.05). Discussion: Our study revealed that MLFs enhance antioxidant enzyme activity, alleviate oxidative damage in ESMCs through the activation of the Nrf2 pathway, and improve mitochondrial respiration and cell energy metabolism. Additionally, we identified five potential antioxidant flavonoid compounds, suggesting their potential incorporation into the equine diet as a strategy to alleviate exercise-induced oxidative stress.

Diazoxide and moderate-intensity exercise improve skeletal muscle function by decreasing oxidants and enhancing antioxidant defenses in hypertensive male rats.

High sodium intake is decisive in the incidence increase and prevalence of hypertension, which has an impact on skeletal muscle functionality. Diazoxide is an antihypertensive agent that inhibits insulin secretion and is an opener of KATP channels (adosine triphosphate sensitive potasium channels). For this reason, it is hypothesized that moderate-intensity exercise and diazoxide improve skeletal muscle function by reducing the oxidants in hypertensive rats. Male Wistar rats were assigned into eight groups: control (CTRL), diazoxide (DZX), exercise (EX), exercise + diazoxide (EX + DZX), hypertension (HTN), hypertension + diazoxide (HTN + DZX), hypertension + exercise (HTN + EX), and hypertension + exercise + diazoxide (HTN + EX + DZX). To induce hypertension, the rats received 8% NaCl dissolved in water orally for 30 days; in the following 8 weeks, 4% NaCl was supplied to maintain the pathology. The treatment with physical exercise of moderate intensity lasted 8 weeks. The administration dose of diazoxide was 35 mg/kg intraperitoneally for 14 days. Tension recording was performed on the extensor digitorum longus and the soleus muscle. Muscle homogenates were used to measure oxidants using fluorescent probe and the activity of antioxidant systems. Diazoxide and moderate-intensity exercise reduced oxidants and increased antioxidant defenses.

Decellularized Bovine Skeletal Muscle Scaffolds: Structural Characterization and Preliminary Cytocompatibility Evaluation.

Skeletal muscle degeneration is responsible for major mobility complications, and this muscle type has little regenerative capacity. Several biomaterials have been proposed to induce muscle regeneration and function restoration. Decellularized scaffolds present biological properties that allow efficient cell culture, providing a suitable microenvironment for artificial construct development and being an alternative for in vitro muscle culture. For translational purposes, biomaterials derived from large animals are an interesting and unexplored source for muscle scaffold production. Therefore, this study aimed to produce and characterize bovine muscle scaffolds to be applied to muscle cell 3D cultures. Bovine muscle fragments were immersed in decellularizing solutions for 7 days. Decellularization efficiency, structure, composition, and three-dimensionality were evaluated. Bovine fetal myoblasts were cultured on the scaffolds for 10 days to attest cytocompatibility. Decellularization was confirmed by DAPI staining and DNA quantification. Histological and immunohistochemical analysis attested to the preservation of main ECM components. SEM analysis demonstrated that the 3D structure was maintained. In addition, after 10 days, fetal myoblasts were able to adhere and proliferate on the scaffolds, attesting to their cytocompatibility. These data, even preliminary, infer that generated bovine muscular scaffolds were well structured, with preserved composition and allowed cell culture. This study demonstrated that biomaterials derived from bovine muscle could be used in tissue engineering.

Effect of Different Exercise Interventions on Grip Strength, Knee Extensor Strength, Appendicular Skeletal Muscle Index, and Skeletal Muscle Index Strength in Patients with Sarcopenia: A Meta-Analysis of Randomized Controlled Trials.

Sarcopenia is a systemic skeletal muscle disease that is more prevalent in older adults. The role of exercise in improving the disease has been demonstrated. However, due to the variety of exercise modalities, it is not clear what type of exercise provides the best benefit. The aim of this meta-analysis was to analyze the effects of different exercise modalities on grip strength, appendicular skeletal muscle index, skeletal muscle index, and knee extensor strength in elderly patients with sarcopenia. The protocol for this evaluation was registered on the PROSPERO website and the databases PubMed, WOS, Cochrane Library, and Embase were searched. Thirteen studies were included in the analysis. The results showed that exercise interventions had positive effects on grip strength and knee extension muscle strength, with resistance training being the most effective. There was no significant improvement in appendicular skeletal muscle index or skeletal muscle index. This study still has limitations. For example, age group and exercise duration were not considered. Future studies should further explore benefits in age groups as well as other relevant outcome indicators.

Inflammatory Cells in Adipose Tissue and Skeletal Muscle of Patients with Peripheral Arterial Disease or Chronic Venous Disease: A Prospective, Observational, and Histological Study.

The main goal of this study was to assess whether the presence of peripheral arterial disease (PAD) correlates with increased inflammatory cell infiltration. An observational, single-centre, and prospective study was conducted from January 2018 to July 2022. Clinical characteristics and anthropometric measures were registered. Consecutive PAD patients with surgical indications for a common femoral artery approach and patients with varicose veins with an indication for surgical ligation of the saphenofemoral junction were included. In both groups, samples of sartorius skeletal muscle, subcutaneous adipose tissue (SAT), and perivascular adipose tissue (PVAT) were collected from the femoral region. We analysed the characteristics of adipocytes and the presence of haemorrhage and inflammatory cells in the samples of PVAT and SAT via haematoxylin-eosin staining. We found that patients with PAD had significantly more inflammatory cells in PVAT [16 (43.24%) vs. 0 (0%) p = 0.008]. Analysing SAT histology, we observed that patients with PAD had significantly more CD45+ leucocytes upon immunohistochemical staining [32 (72.73%) vs. 3 (27.27%) p = 0.005]. Upon analysing skeletal muscle histology with haematoxylin-eosin staining, we evaluated skeletal fibre preservation, as well as the presence of trauma, haemorrhage, and inflammatory cells. We registered a significantly higher number of inflammatory cells in patients with PAD [well-preserved skeletal fibres: PAD = 26 (63.41%) vs. varicose veins = 3 (37.50%) p = 0.173; trauma: PAD = 4 (9.76%) vs. varicose veins = 2 (25.00%) p = 0.229; haemorrhage: PAD = 6 (14.63%) vs. varicose veins = 0 (0%) p = 0.248; inflammatory cells: PAD = 18 (43.90%) vs. varicose veins = 0 (0%) p = 0.018]. Patients with PAD had a higher number of inflammatory cells in skeletal muscle and adipose tissue (PVAT and SAT) when compared with those with varicose veins, emphasizing the role of inflammation in this group of patients.

Exploring Possible Links: Thigh Muscle Mass, Apolipoproteins, and Glucose Metabolism in Peripheral Artery Disease-Insights from a Pilot Sub-Study following Endovascular Treatment.

Peripheral artery disease (PAD) compromises walking and physical activity, which results in further loss of skeletal muscle. The cross-sectional area of the thigh muscle has been shown to be correlated with systemic skeletal muscle volume. In our previous pilot study, we observed an increase in thigh muscle mass following endovascular treatment (EVT) in patients with proximal vascular lesions affecting the aortoiliac and femoropopliteal arteries. Considering the potential interactions between skeletal muscle, lipid profile, and glucose metabolism, we aimed to investigate the relationship between thigh muscle mass and apolipoproteins as well as glucose metabolism in PAD patients undergoing EVT. This study is a prespecified sub-study conducted as part of a pilot study. We prospectively enrolled 22 symptomatic patients with peripheral artery disease (PAD) and above-the-knee lesions, specifically involving the blood vessels supplying the thigh muscle. The mid-thigh muscle area was measured with computed tomography before and 6 months after undergoing EVT. Concurrently, we measured levels of apolipoproteins A1 (Apo A1) and B (Apo B), fasting blood glucose, 2 h post-load blood glucose (using a 75 g oral glucose tolerance test), and glycated hemoglobin A1c (HbA1c). Changes in thigh muscle area (delta muscle area: 2.5 ± 8.1 cm2) did not show significant correlations with changes in Apo A1, Apo B, fasting glucose, 2 h post-oral glucose tolerance test blood glucose, HbA1c, or Rutherford classification. However, among patients who experienced an increase in thigh muscle area following EVT (delta muscle area: 8.41 ± 5.93 cm2), there was a significant increase in Apo A1 (pre: 121.8 ± 15.1 mg/dL, 6 months: 136.5 ± 19.5 mg/dL, p < 0.001), while Apo B remained unchanged (pre: 76.4 ± 19.2 mg/dL, 6 months: 80.5 ± 4.9 mg/dL). Additionally, post-oral glucose tolerance test 2 h blood glucose levels showed a decrease (pre: 189.7 ± 67.5 mg/dL, 6 months: 170.6 ± 69.7 mg/dL, p = 0.075). Patients who exhibited an increase in thigh muscle area demonstrated more favorable metabolic changes compared to those with a decrease in thigh muscle area (delta muscle area: -4.67 ± 2.41 cm2). This pilot sub-study provides insights into the effects of EVT on thigh muscle, apolipoproteins, and glucose metabolism in patients with PAD and above-the-knee lesions. Further studies are warranted to validate these findings and establish their clinical significance. The trial was registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN000047534).

Comparing the Impacts of Testosterone and Exercise on Lean Body Mass, Strength and Aerobic Fitness in Aging Men.

BACKGROUND: Based on the largely untested premise that it is a restorative hormone that may reverse the detrimental impacts of aging, prescription of testosterone (T) has increased in recent decades despite no new clinical indications. It is apparent that middle-aged and older men with low-normal serum T levels are considering T supplementation as an anti-aging strategy. At the same time, there is evidence that physical activity (PA) is at historical lows in the Western world. In this review, we compare the impacts of T treatment aimed at achieving physiological T concentrations in middle-aged and older men, alongside the impacts of ecologically relevant forms of exercise training. The independent, and possible combined, effects of T and exercise therapy on physiological outcomes such as aerobic fitness, body composition and muscular strength are addressed. MAIN BODY: Our findings suggest that both T treatment and exercise improve lean body mass in healthy older men. If improvement in lean body mass is the primary aim, then T treatment could be considered, and the combination of T and exercise may be more beneficial than either in isolation. In terms of muscle strength in older age, an exercise program is likely to be more beneficial than T treatment (where the dose is aimed at achieving physiological concentrations), and the addition of such T treatment does not provide further benefit beyond that of exercise alone. For aerobic fitness, T at doses aimed at achieving physiological concentrations has relatively modest impacts, particularly in comparison to exercise training, and there is limited evidence as to additive effects. Whilst higher doses of T, particularly by intramuscular injection, may have larger impacts on lean body mass and strength, this must be balanced against potential risks. CONCLUSION: Knowing the impacts of T treatment and exercise on variables such as body composition, strength and aerobic fitness extends our understanding of the relative benefits of physiological and pharmacological interventions in aging men. Our review suggests that T has impacts on strength, body composition and aerobic fitness outcomes that are dependent upon dose, route of administration, and formulation. T treatment aimed at achieving physiological T concentrations in middle-aged and older men can improve lean body mass, whilst exercise training enhances lean body mass, aerobic fitness and strength. Men who are physically able to exercise safely should be encouraged to do so, not only in terms of building lean body mass, strength and aerobic fitness, but for the myriad health benefits that exercise training confers.

Oncostatin M signaling drives cancer-associated skeletal muscle wasting.

Progressive weakness and muscle loss are associated with multiple chronic conditions, including muscular dystrophy and cancer. Cancer-associated cachexia, characterized by dramatic weight loss and fatigue, leads to reduced quality of life and poor survival. Inflammatory cytokines have been implicated in muscle atrophy; however, available anticytokine therapies failed to prevent muscle wasting in cancer patients. Here, we show that oncostatin M (OSM) is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes using the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing reveals the induction of various muscle atrophy-related genes, including Atrogin1. OSM overexpression in mice causes muscle wasting, whereas muscle-specific deletion of the OSM receptor (OSMR) and the neutralization of circulating OSM preserves muscle mass and function in tumor-bearing mice. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the therapeutic targeting of this pathway may be useful in preventing muscle wasting.

Grape seed proanthocyanidin extract promotes skeletal muscle fiber type transformation through modulation of cecal microbiota and enhanced butyric acid production.

The conversion of fast-twitch fibers into slow-twitch fibers within skeletal muscle plays a crucial role in improving physical stamina and safeguarding against metabolic disorders in individuals. Grape seed proanthocyanidin extract (GSPE) possesses numerous pharmacological and health advantages, effectively inhibiting the onset of chronic illnesses. However, there is a lack of research on the specific mechanisms by which GSPE influences muscle physiology and gut microbiota. This study aims to investigate the role of gut microbiota and their metabolites in GSPE regulation of skeletal muscle fiber type conversion. In this experiment, 54 male BALB/c mice were randomly divided into three groups: basal diet, basal diet supplemented with GSPE, and basal diet supplemented with GSPE and antibiotics. During the feeding period, glucose tolerance and forced swimming tests were performed. After euthanasia, samples of muscle and feces were collected for analysis. The results showed that GSPE increased the muscle mass and anti-fatigue capacity of the mice, as well as the expression of slow-twitch fibers. However, the beneficial effects of GSPE on skeletal muscle fibers disappeared after adding antibiotics to eliminate intestinal microorganisms, suggesting that GSPE may play a role by regulating intestinal microbial structure. In addition, GSPE increased the relative abundance of Blautia, Muribaculaceae, and Enterorhabdus, as well as butyrate production. Importantly, these gut microbes exhibited a significant positive correlation with the expression of slow-twitch muscle fibers. In conclusion, supplementation with GSPE can increase the levels of slow-twitch fibers by modulating the gut microbiota, consequently prolonging the duration of exercise before exhaustion. PRACTICAL APPLICATION: This research suggests that grape seed proanthocyanidin extract (GSPE) has potential applications in improving physical stamina and preventing metabolic disorders. By influencing the gut microbiota and increasing butyric acid production, GSPE contributes to the conversion of fast-twitch muscle fibers into slow-twitch fibers, thereby enhancing anti-fatigue capacity and exercise endurance. While further studies are needed, incorporating GSPE into dietary supplements or functional foods could support individuals seeking to optimize their exercise performance and overall metabolic health.

Muscle strength, quantity and quality and muscle fat quantity and their association with oxidative stress in patients with facioscapulohumeral muscular dystrophy: Effect of antioxidant supplementation.

The purpose of this study was to identify causes of quadriceps muscle weakness in facioscapulohumeral muscular dystrophy (FSHD). To this aim, we evaluated quadriceps muscle and fat volumes by magnetic resonance imaging and their relationships with muscle strength and oxidative stress markers in adult patients with FSHD (n = 32) and healthy controls (n = 7), and the effect of antioxidant supplementation in 20 of the 32 patients with FSHD (n = 10 supplementation and n = 10 placebo) (NCT01596803). Compared with healthy controls, the dominant quadriceps strength and quality (muscle strength per unit of muscle volume) were decreased in patients with FSHD. In addition, fat volume was increased, without changes in total muscle volume. Moreover, in patients with FSHD, the lower strength of the non-dominant quadriceps was associated with lower muscle quality compared with the dominant muscle. Antioxidant supplementation significantly changed muscle and fat volumes in the non-dominant quadriceps, and muscle quality in the dominant quadriceps. This was associated with improved muscle strength (both quadriceps) and antioxidant response. These findings suggest that quadriceps muscle strength decline may not be simply explained by atrophy and may be influenced also by the muscle intrinsic characteristics. As FSHD is associated with increased oxidative stress, supplementation might reduce oxidative stress and increase antioxidant defenses, promoting changes in muscle function.

The tourniquet's effects on skeletal muscle during total knee arthroplasty.

This study investigates the impact of perioperative tourniquet on skeletal muscle cells during total knee arthroplasty (TKA) and its effects on the gene expression of apoptotic, inflammatory, and angiogenic pathways. The randomized controlled trial included 44 patients undergoing TKA. The patients were randomized to undergo surgery with (n = 23) or without (n = 21) tourniquet. The tourniquet was inflated before skin incision and deflated before wound closure in the tourniquet group. Biopsies from the lateral vastus muscle were obtained from both groups before wound closure and 8 weeks after surgery. The messenger ribonucleic acid (mRNA) expression and protein levels of angiopoietin-like 4 (ANGPTL4), Hypoxia-inducible Factor 1α, and Vascular Endothelial Growth Factor Alpha (VEGF-A) in the biopsies were examined by reverse transcription-quantitative polymerase chain reaction and tissue microarray, respectively. Differences in mean values (ΔCt for mRNA expression and staining positivity for protein expression) were compared with t-tests. The apoptotic marker BID and the angiogenic marker VEGF-A were significantly lower in the tourniquet group compared to the control group (p = 0.03, p = 0.047). However, there was a significant upregulation of VEGF-A 8 weeks after surgery in the tourniquet group compared to perioperative biopsies (p = 0.002), indicating persistent changes. A significant upregulation in protein expression of the angiogenic marker ANGPTL4 was found perioperatively in the tourniquet group (p = 0.02). Our results demonstrate that the angiogenic gene expression is significantly altered by the tourniquet, the effects of which might contribute to postoperative interstitial edema, increased pain, and decreased muscle strength. These effects could lead to delayed rehabilitation and ultimately reduced patient satisfaction after TKA.