Search Results (6,539)

Leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is a well-characterized myokine with pleiotropic regulatory effects on skeletal muscle. LIF modulates several fundamental cellular processes, including myoblast proliferation, apoptosis, angiogenesis, and energy metabolism. Exercise upregulates LIF expression in skeletal muscle, thereby promoting satellite cell activation, proliferation, myoblast differentiation, and angiogenesis, facilitating physiological muscle hypertrophy, and suppressing myocyte apoptosis and muscle atrophy. In addition, LIF plays a critical role in modulating the inflammatory and extracellular matrix remodeling following exercise-induced muscle damage, thereby supporting efficient muscle repair and regeneration. This review elaborates on the biological mechanisms by which LIF regulates skeletal muscle atrophy and contributes to the enhancement of skeletal muscle function. It also highlights the biological characteristics of myogenic LIF and discusses future directions for basic and applied research on exercise interventions targeting LIF signaling pathways. Full article

Physical inactivity contributes to type 2 diabetes (T2D), but the molecular links between exercise and metabolic improvement remain incompletely understood. We meta-analyzed genome-wide association studies of vigorous physical activity and T2D (combined n ≈ 1.95 million) and integrated eQTL/sQTL maps with single-cell and spatial transcriptomic datasets to connect genetic risk with tissues, cell types, and regulatory programs. Tissue and cell-type enrichment, colocalization, and network analyses were performed. Computational findings were further examined in male 10-week-old C57BL/6J mice with high-fat diet-induced diabetes. After 1 week of acclimatization, mice were randomly assigned to normal chow, high-fat diet, or high-fat diet plus exercise groups (n = 6 per group; high-fat diet with 60% of total energy from fat). The exercise intervention consisted of treadmill running (10 m/min for 50 min per day, 5 days per week, total 16 weeks), followed by metabolic phenotyping, skeletal muscle histology, bulk RNA sequencing, alternative splicing analysis, and RT-qPCR of Mau2 isoforms. Exercise- and T2D-associated variants showed joint enrichment in skeletal muscle and adipose eQTL/sQTL signals. Integrated single-cell analyses prioritized fibro-adipogenic progenitors and endothelial cells, and identified an extracellular matrix- and collagen-related module in fibro-adipogenic progenitors associated with both exercise and T2D. Mau2 emerged as a shared candidate gene with tissue-specific splicing signals. In diabetic mice, exercise improved glucose homeostasis and muscle fiber structure, and reduced Mau2 intron retention in skeletal muscle without changing total Mau2 expression. These findings support a multiscale framework linking exercise-responsive regulation to T2D-related tissue remodeling and splicing plasticity. Full article

Voltage-gated ion channels are central regulators of cardiac, neuronal, and skeletal muscle excitability, and their dysfunction underlies a wide spectrum of channelopathies, including arrhythmias and neuromuscular disorders. While conventional ion channel therapeutics typically target a single pore-binding site, emerging evidence supports the therapeutic potential of polypharmacological compounds capable of modulating multiple channel subtypes. ARumenamides represent a novel class of sulfonamide-based ligands originally identified as fenestration-targeting sodium channel modulators; however, their cross-family binding mechanisms and multitarget potential remain incompletely defined. Here, we employed an integrated structure-based computational workflow combining molecular docking, in silico ADMET profiling, and long-timescale (250 ns) molecular dynamics simulations to systematically evaluate 20 ARumenamide derivatives across 15 voltage-gated sodium, calcium, and potassium channel structures. Docking analyses revealed broad multitarget binding profiles, with several compounds exhibiting high predicted affinity across cardiac, neuronal, and skeletal muscle channel isoforms. ADMET predictions demonstrated favorable intestinal absorption and metabolic safety for most candidates, although solubility and mutagenicity liabilities were identified for select derivatives. Detailed molecular dynamics simulations of prioritized compounds (AR-310, AR-769, and AR-946) uncovered site-specific binding behaviors and conformational effects. AR-769 exhibited exceptional stability at both fenestration and central pore sites of Cav1.2, associated with persistent hydrogen-bond networks, reduced protein flexibility, and a well-defined free energy minimum. In contrast, AR-310 and AR-946 displayed selective stability within Nav1.4 fenestrations and the Kv4.3 central pore, respectively, highlighting how subtle chemical features bias binding site preference and dynamic retention. Collectively, these findings establish a structure–dynamics framework for rational design of ARumenamide-based multitarget ion channel modulators. Our results demonstrate that fenestration-focused binding can support sustained ligand engagement without obligatory pore occlusion, offering a mechanistically distinct strategy for developing next-generation polypharmacological therapeutics for cardiac and neuromuscular disorders. Full article

Skeletal muscle loss resulting from traumatic injury, sarcopenia, and myopathies remains a major clinical challenge due to the limited regenerative capacity of adult muscle tissue. This review systematically examines advanced biomedical therapeutic approaches to restoring muscle mass and function, including gene therapy, microRNA, cell-based strategies, and tissue engineering. Key mechanisms of muscle histogenesis and regeneration are discussed, with emphasis on the roles of satellite cells, growth factors (IGF-1, VEGF), and transcriptional regulators. Preclinical studies demonstrate that viral and non-viral delivery of myogenic factors can enhance muscle repair, reduce fibrosis, and improve functional outcomes. However, translation to clinical practice is hindered by challenges such as immune responses, inadequate reinnervation, and the complexity of replicating native tissue architecture. Emerging strategies combining gene delivery with rehabilitation, immunomodulation, or exosome therapy show synergistic effects. Although clinical trials targeting sarcopenia and muscle defects using anti-myostatin antibodies, stem cell-derived products, and acellular scaffolds have reported modest gains in strength and lean mass, no definitive regenerative therapy has been approved. While significant progress has been made, achieving full structural and functional muscle regeneration will require combinatorial approaches that address vascularization, innervation, and the inflammatory microenvironment. Full article

Type 2 diabetes (T2D) is a multifactorial metabolic disorder characterized by chronic hyperglycemia, insulin resistance, and progressive β-cell dysfunction. Chronic hyperglycemia in T2D causes multi-organ and systemic damage, leading to a wide range of complications, including cardiovascular disease and metabolic dysfunction-associated steatotic liver disease (MASLD). Brown seaweeds are increasingly recognized as promising marine-derived functional foods because they contain structurally unique bioactive compounds, including fucoidan, alginate, phlorotannins, and fucoxanthin. A growing body of evidence suggests that these compounds influence glucose homeostasis through multiple mechanisms, including improvement of pancreatic β-cell function, regulation of gut-mediated metabolic processes, and modulation of glucose metabolism and insulin signaling in the liver, adipose tissue, and skeletal muscle, and attenuation of chronic inflammation and oxidative stress. Brown seaweed-derived bioactive compounds have also been reported to improve abnormal lipid metabolism, a key pathological process implicated in metabolic disorders associated with T2D, including MASLD. This review provides an overview of the antidiabetic potential of brown seaweeds, with a particular focus on the mechanisms of action of their major bioactive compounds, including fucoidan, alginate, phlorotannins, and fucoxanthin. Full article

Background: Sarcopenia, characterized by progressive loss of skeletal muscle mass and function, is becoming increasingly prevalent with the global population aging. Computed tomography (CT) is widely used for muscle assessment; however, concerns regarding radiation exposure have prompted interest in lower-dose imaging protocols. This study investigated the performance of radiomics-based machine learning (ML) models for sarcopenia detection using abdominal CT (APCT) and low-dose CT (LDCT). Methods: Radiomics features were extracted from CT images following skeletal muscle segmentation, and ML models were developed using logistic regression, support vector machine, and random forest. Model performance was evaluated using fivefold cross-validation with out-of-fold predictions. Results: The random forest model demonstrated the best performance among the evaluated models, achieving an area under the receiver operating characteristic curve of 0.720 (95% CI: 0.532–0.881) for APCT and 0.692 (95% CI: 0.573–0.801) for LDCT. Model interpretation using SHapley Additive exPlanations analysis identified several intensity-based radiomics features, including TotalEnergy, as important contributors to sarcopenia prediction. Conclusions: These findings suggest that radiomics features derived from LDCT images may provide useful information for sarcopenia detection. Because LDCT is widely used in clinical settings such as lung cancer screening, radiomics analysis of LDCT images may offer an additional opportunity for opportunistic sarcopenia assessment. Full article

Sarcopenia is increasingly invoked as a determinant of treatment-related toxicity, perioperative morbidity, treatment intolerance, and survival in oncology; however, contemporary international consensus frameworks define sarcopenia as a multidimensional neuromuscular syndrome centered on impaired muscle strength, physical performance, and muscle quality, whereas most oncologic studies operationalize sarcopenia using computed tomography (CT)-derived skeletal muscle mass alone. In this context, muscle quantity is effectively employed as a diagnostic surrogate for a function-centered syndrome. CT-defined skeletal muscle depletion—more precisely described as myopenia—remains a reproducible and clinically informative structural biomarker, yet defining sarcopenia by muscle mass alone aggregates biologically heterogeneous phenotypes, including neuromuscular dysfunction, inflammation-driven cachexia, and substrate-related malnutrition. Such surrogate-based definitions contribute to variable prevalence estimates, inconsistent prognostic associations, and interpretive instability across studies. Clinically, reliance on CT-based muscle mass as a surrogate for sarcopenia may influence chemotherapy dosing, perioperative risk stratification, and supportive care allocation without direct assessment of neuromuscular function; in research settings, mass-based definitions may dilute treatment effects in exercise or nutritional trials and complicate meta-analytic synthesis by conflating structural and functional constructs. This analysis does not question the value of radiologic muscle assessment but argues that CT-derived muscle mass should be recognized as a structural biomarker within a multidimensional framework rather than as a standalone diagnostic surrogate for sarcopenia. A tiered, oncology-adapted approach integrating functional assessment, muscle quality, and relevant metabolic context may enhance risk discrimination, improve trial design, and strengthen translational precision in supportive oncology. Full article

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a complex and debilitating disorder with limited treatment options. Camel milk (CM), known for its rich nutrients and anti-fatigue properties, may offer multi-target benefits for managing this condition. This study utilized an integrated approach combining metabolomics, network pharmacology, and animal experiments. CM metabolites were profiled and screened via ADME. Potential targets were predicted and intersected with CFS/ME-associated genes. Male BALB/c mice were subjected to chronic restraint and forced swimming to evaluate the effects of CM (1000 mg/kg) on behavioral, inflammatory, neuroendocrine, and metabolic parameters. CM administration significantly improved exhaustive swimming time and reduced immobility. It attenuated systemic inflammation (restored IL-10), normalized brain CREB and DRD2/OPRM1 mRNA, and enhanced skeletal muscle AKT/GLUT4 expression and glycogen levels. Camel milk alleviates CFS/ME symptoms through the multi-component, multi-target regulation of neuroendocrine, inflammatory, and energy metabolism pathways. These preclinical findings suggest that CM may have potential as a supportive nutritional intervention for alleviating chronic fatigue, pending validation in human studies. Full article

Background/Objectives: Lung cancer remains a leading cause of cancer-related mortality and is characterized by complex tumor–host interactions, including systemic inflammation, metabolic dysregulation, and immune imbalance. This study aimed to evaluate whether a diagnosis of anemia reflects underlying inflammatory burden and to explore phenotype-based interactions between anemia, inflammation, and muscle depletion in lung cancer patients. Methods: A retrospective cohort study was conducted, including 70 patients diagnosed with lung cancer between 2019 and 2023. Anemia was defined using standard hemoglobin thresholds (<12 g/dL in women, <13 g/dL in men). Systemic inflammation was assessed using complete blood count-derived indices (NLR, PLR, SII, SIRI, and AISI), both individually and combined into a cumulative inflammatory score. Sarcopenia was evaluated through CT-based quantification of skeletal muscle area at the L3 level. Patients were stratified into four phenotypes based on anemia status, inflammatory burden, and sarcopenia. Statistical analyses like Mann–Whitney U, Kruskal–Wallis with Dunn post hoc testing, and univariate logistic regression were used. Results: Anemia was present in 44.3% of patients and was associated with a significantly higher inflammatory score compared to non-anemic patients (median 5 [IQR 4–5] vs. 4 [3–5], p = 0.024). Among inflammatory markers, PLR was significantly associated with anemia (OR = 4.94, 95% CI: 1.57–15.52, p = 0.004). The cumulative inflammatory score showed a non-significant association with anemia (OR = 1.28, 95% CI: 0.93–1.75, p = 0.124). Phenotype-based analysis revealed significant differences in skeletal muscle area (p = 0.004), with the sarcopenic-inflammatory phenotype exhibiting significantly lower muscle mass compared to other groups. No associations were observed between phenotypes and tumor stage or histological subtype. Conclusions: Anemia in lung cancer patients is closely associated with systemic inflammation and may reflect underlying biological vulnerability rather than tumor-specific characteristics. A phenotype-based approach integrating anemia, inflammatory markers, and sarcopenia provides a more comprehensive understanding of disease heterogeneity and may improve risk stratification. Further studies are needed to validate these findings and assess their prognostic implications. Full article

We evaluated the effects of a 12-week multidisciplinary program on health-related physical fitness and depressive symptoms in overweight and obese women (aged 45–64 years) diagnosed with noncommunicable diseases (NCDs). Methods: A longitudinal, pre-experimental, proof-of-concept study was conducted. Thirty-one women completed multidisciplinary interventions [nutritional education or psychoeducation (each once a week), and resistance training (twice a week)]. Body composition (bioelectrical impedance), physical fitness (maximal isometric strength, lower limb strength–endurance, flexibility, and aerobic fitness), and depressive symptoms (PHQ-9) were measured at baseline and post-intervention. Results: Significant improvements in body composition were observed in terms of lean mass (Δ% = 3.7; p < 0.001), fat-free mass (Δ% = 3.6; p < 0.001), skeletal muscle mass (Δ% = 5.2; p < 0.001), fat mass (Δ% = −3.5; p < 0.001), body fat percentage (Δ% = −4.7; p < 0.001), and visceral fat level (Δ% = −2.9; p = 0.012). Physical fitness exhibited a large effect size in the chair stand test (d = 0.91) and the 6 min walk test (d = 1.22). Depressive symptom scores substantially decreased (p < 0.001). Conclusion: The program demonstrated potential efficacy in mitigating sarcopenic obesity, enhancing functional capacity, and reducing depressive symptoms, indicating potential clinical viability for the integrated management of multimorbidity. Full article

Background/Objectives: Remnant cholesterol (remnant-C), derived from triglyceride-rich lipoproteins, is an important risk factor for cardiometabolic diseases. Given the metabolic link between dyslipidemia and skeletal muscle dysfunction, we aimed to evaluate the association between remnant-C and two key components of sarcopenia—low muscle mass and myosteatosis (ectopic fat deposition in skeletal muscle). Methods: This cross-sectional study included 11,570 patients who underwent abdominal computed tomography (CT) for health check-ups. Remnant-C was calculated as total cholesterol minus low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. We conducted multivariable logistic and linear analyses to assess the association between remnant-C and low muscle mass, defined as appendicular skeletal muscle mass divided by body mass index. Additional analysis examined the relationship between remnant-C and myosteatosis, defined using the NAMA (normal attenuation muscle area) divided by TAMA (total abdominal muscle area) index, a novel index derived from muscle quality mapping of abdominal CT scans. Results: Low muscle mass was observed in 244 males (3.9%) and 74 females (1.4%). Myosteatosis affected 950 males (15.0%) and 800 females (15.3%). There was an increasing prevalence of both low muscle mass and myosteatosis across remnant-C quartiles. The multivariate-adjusted odds ratios (ORs) for low muscle mass in the highest remnant-C quartile compared with the lowest quartile were 2.17 (95% confidence interval [CI] 1.45–3.26) for males and 1.37 (95% CI 0.68–2.76) for females. The corresponding ORs for myosteatosis were 1.37 (95% CI 1.11–1.69) for males and 1.24 (95% CI 0.96–1.59) for females. Conclusions: Elevated remnant-C level is associated with low muscle mass and myosteatosis, especially in male patients. Individuals with higher remnant-C levels may warrant comprehensive evaluation for skeletal muscle health. Full article

As primary sites for oxygen consumption and energy production via oxidative phosphorylation (OXPHOS), mitochondria play a central role in the regulation of bioenergetics and generation of key metabolic intermediates for myogenic cell growth. Common methods to study mitochondria and their metabolism typically rely on population-level analyses, which can mask potential differences in individual cells. In this study, we used various imaging approaches to investigate the interplay between intracellular oxygenation, mitochondrial metabolism and dynamics in a model of myogenic differentiation. Fluorescence imaging of intracellular oxygen revealed that myogenic differentiation is accompanied by progressive shifts in intracellular oxygenation that depend upon and reflect changes in mitochondrial metabolism (i.e., higher oxygen consumption and adenosine triphosphate (ATP) production). By measuring intracellular oxygenation, we showed that mitochondrial metabolism reduces oxygen availability in the cytosol and the nucleus. Real-time redox imaging at the single-cell level further highlighted substantial metabolic heterogeneity and a shift toward OXPHOS as differentiation progressed. Morphological analyses revealed that during myogenic differentiation, mitochondria increase in size while becoming less mobile and overlapping less with microtubules. Overall, this study illustrates the value of combining complementary imaging approaches to provide a comprehensive single-cell perspective on mitochondrial metabolism, remodeling and spatial organization during myogenesis. Full article

To maintain homeostatic conditions and optimal function during stressors, mitochondria initiate retrograde signaling. The mitochondrial integrated stress response (ISR) and unfolded protein response (UPR^mt) are critical quality control mechanisms activated during instances of mitochondrial perturbations. Restoration of mitochondrial homeostasis is orchestrated by three transcription factors, ATF4, CHOP, and ATF5, which upregulate protective genes to counteract stress. As the health and function of skeletal muscle are heavily dependent on a highly adaptive mitochondrial network, defining how mitochondrial health is maintained across various conditions is essential. Although several studies demonstrate the importance of these responses following instances of stress, the signaling mechanisms required to initiate such pathways remain poorly characterized in skeletal muscle. This review examines how the mitochondrial ISR/UPR^mt and related transcription factors respond to organellar stress by emphasizing the molecular events that occur during exercise, aging and muscle disuse. By consolidating the literature, this work aims to highlight the current understanding of mitochondrial stress response signaling within skeletal muscle and thus emphasize areas for future research and potential therapeutic strategies during divergent metabolic conditions. Full article

Muscle oxygen nation impairment, defined as a mismatch between oxygen delivery, distribution, and oxidative utilization in active skeletal muscle, contributes to exercise intolerance and functional decline. Near-infrared spectroscopy (NIRS) has emerged as the leading non-invasive tool for monitoring local muscle oxygenation, but its clinical translation and optimal exercise-based management remain incompletely defined. This scoping review aimed to (1) synthesize the pathophysiology of muscle oxygenation impairment across the oxygen transport cascade, (2) evaluate NIRS-based diagnostic protocols, and (3) review exercise-based interventions targeting muscle oxygenation. The review followed PRISMA-ScR guidelines and was prospectively registered in OSF (DOI: 10.17605/OSF.IO/QW8R3) and PROSPERO (CRD420261365040). PubMed, Web of Science, Scopus, Cochrane CENTRAL, EMBASE, PEDro, and ClinicalTrials.gov were searched through to April 2026. Methodological quality was appraised using the PEDro scale, the Downs and Black checklist, and the Newcastle–Ottawa Scale. A total of 61 studies (2003–2025) were included, with fair-to-good methodological quality (PEDro 3–8, mean 5.3; Downs and Black 15–24, mean 18.6; Newcastle–Ottawa 5–8, mean 6.5). Regarding pathophysiology, muscle oxygenation impairment is a cascade-level phenomenon with four mechanistically distinct phenotypes corresponding to the dominant site of impairment, each with characteristic NIRS signatures. Regarding diagnostic assessment, NIRS has shown value in selected contexts including a validated threshold for peripheral artery disease, but most studies report group-level correlations without deriving receiver operating characteristic curves at validated thresholds, which together with device and calibration heterogeneity limits clinical translation. Regarding exercise-based interventions, adaptations align with the underlying cascade lesion, sprint and high-intensity interval training enhance oxidative capacity, while walking-based and vascular-targeted programs preferentially improve microvascular function. These findings support a unifying framework in which the site of cascade impairment guides diagnostic protocol selection and exercise prescription. The proposed cascade lesion phenotyping schema is hypothesis-generating and requires prospective validation. Full article