Skeletal Muscle Structure Research Articles

Evaluation of the toxicity potential of exercise and atorvastatin/metformin combination therapy on STZ-diabetic rats.

Exercise is recommended for individuals with diabetes, and metformin and atorvastatin are commonly prescribed to diabetic patients. However, these two drugs have potential effects that may lead to toxicity in the skeletal muscle system. Therefore, the effects and potential interactions of combining these two drugs on skeletal muscle performance and structure were investigated in vivo in an experimental diabetes model. Male Wistar rats were divided into six groups: a sedentary control group (N) and five treatment groups-exercise (C), diabetes (D), diabetes with metformin (MET), diabetes with atorvastatin (ATO), and diabetes with metformin and atorvastatin (MET + ATO). In the diabetes model experimentally created with streptozotocin (STZ; 45mg/kg, i.p.) and metformin (300mg/kg/day), atorvastatin (10mg/kg/day) was administered to drug groups by gavage during the 4-week study period. The rats were allowed to run (at moderate level) for 30min, 5days a week, on the treadmill. At the end of the study, blood samples and gastrocnemius muscle tissues of the rats were obtained under ketamine anesthesia (100mg/kg; i.p). The effects of combining exercise and medication on skeletal muscle were assessed by examining the levels of significant biomarkers including PGC-1α, UCP-3, and MyHCs, as well as analyzing oxidative stress/antioxidant capacity parameters in muscle tissue samples. Additionally, relevant biochemical indicators were determined in serum samples. The quantity and morphology of mitochondria in muscle tissue were assessed using transmission electron microscopy. It was observed in the study that some toxic effects associated with the use of drugs alone were reduced by combination therapy. It is thought that this study will contribute to the literature in the evaluation of the effects of drugs and their combined use in Type 1 diabetes under exercise conditions.

Muscular strength, endothelial function and cognitive disorders: state of the art.

In recent years, the ageing population has increasingly grown. This process carries a range of pathophysiological changes involving alterations in the skeletal muscle, vascular endothelium and brain function, becoming an important risk factor for developing cognitive disorders and cardiovascular diseases. With ageing, there is a decrease in muscle mass and muscle strength, and a relationship between muscle strength decrease and cognitive decline has been shown. Lower handgrip strength has been linked to memory impairment, lower global cognitive function, decreased attention and reduced visuospatial abilities in the elderly, but understanding of the underlying mechanisms that explain the link between altered skeletal muscle function and structure, endothelial dysfunction, and the role of endothelial dysfunction in the onset of cognitive disorders has been scarcely explored. This review aims to detail the cellular and molecular mechanisms by which the progressive changes associated with ageing can alter healthy skeletal muscle and endothelial function, creating an environment of oxidative stress, inflammation and mitochondrial dysfunction. These changes can lead to reduced muscle strength, and the secretion of detrimental endothelial factors, resulting in endothelial dysfunction, blood-brain barrier disruption, and damage to neurons and microglia, ultimately accelerating the onset of cognitive disorders in the elderly. In addition, we aimed to describe the mechanisms that potentially explain how preserving muscular function with resistance training could prevent brain function deterioration, including the production of different factors that allow an improved endothelial function, haemodynamic parameters and brain plasticity, ultimately delaying the onset of cognitive impairment and chronic diseases.

Muscle RING-finger proteins (MuRF) regulate protein kinase A activity via retrograde vesicular transport of PKA RI-alpha

Abstract Background Muscle RING finger (MuRF) proteins are muscle-restricted E3 ubiquitin ligases that control protein degradation in striated muscles. MuRF proteins have coordinate functions for maintenance of striated muscle structure and function that depends on their target proteins. MuRF1 is a key enzyme in muscle atrophy. MuRF2 and MuRF3 bind to and stabilize microtubules which affects striated muscle differentiation and contraction. Although some MuRF-interaction partners have been described only few have been proven to be targeted for proteasomal degradation. To better understand the function of MuRF proteins, we set out to identify and functionally characterize novel MuRF target proteins. Methods and Results Stable isotope labeling of amino acids in cell culture followed by affinity purification and quantitative mass spectrometry analysis (SILAC-AP-MS) was used to identify the interactome of MuRF proteins. We identified the mammalian retromer subunit sorting nexin 5 (SNX5) that is involved in subcellular trafficking as a novel MuRF2 and MuRF3 interaction partner. Coimmunoprecipitation experiments and immunocytochemistry confirmed physical interaction and colocalization between SNX5 and MuRF2 or MuRF3. The interaction domains were mapped. MuRF2, MuRF3 and SNX5 were colocalized to early endosomes at microtubules in myocytes. MuRF2 mediated the ubiquitin proteasome system-dependent degradation of SNX5 in a RING-finger dependent manner, whereas MuRF3 stabilized SNX5. Using mass spectrometry, we identified the regulatory subunit of protein kinase A (PKA-RI-α) as a cargo of SNX5 coated early endosomes in myocytes. CRISPR-Cas9 and siRNA experiments showed that SNX5 regulates PKA activity by stabilizing PKA-RI-α in myocytes. Deletion of SNX5 resulted in PKA activation and inhibition of the HDAC5-MEF2 axis that disturbed myogenic differentiation. Conclusion MuRF2 and MuRF3 play opposing roles in SNX5-mediated retrograde transport of early endosomes along microtubules in myocytes. This mechanism is involved in regulation of PKA catalytic activity via stabilization of PKA-RI-α and controls differentiation of striated muscles.

Bioactive MXene hydrogel promotes structural and functional regeneration of skeletal muscle through improving autophagy and muscle innervation

Complete skeletal muscle regeneration after traumatic injuries remains a challenge due to impaired regenerative capability and dysregulated microenvironments. Autophagy plays a crucial role in the muscle regeneration process by regulating myogenic and non-myogenic cells. Herein, we report a bioactive MXene hydrogel (FPGM) capable of upregulating autophagy and increasing muscle innervation to restore skeletal muscle structure and function. FPGM possessed excellent electrical conductivity, tissue adhesive ability and antioxidation, which could eliminate excess reactive oxygen species to reduce oxidative stress and decrease the secretion of pro-inflammatory cytokine. FPGM upregulated the autophagy level of myoblasts and promoted the migration and tube formation of endothelial cells as well as myogenic differentiation with negligible toxicity. FPGM accelerated muscle fiber formation and skeletal muscle regeneration by improving autophagy, which could regulate microenvironment through raising M2 macrophages to alleviate excessive inflammation, facilitating angiogenesis and decreasing fibrous scar tissue formation in vivo. Importantly, FPGM could efficiently restore muscle function by improving muscle innervation, tibialis anterior compound muscle action potential amplitude and neuromuscular conduction. This work demonstrates that bioactive MXene hydrogel should be a promising candidate for complete skeletal muscle regeneration.

Tubular Aggregates as a Marker of Aging in Skeletal Muscle.

Tubular aggregates (TA) are skeletal muscle structures that arise from the progressive accumulation of sarcoplasmic reticulum proteins, mainly with aging. Muscle regeneration plays a role in TA formation. TA quantification may aid in the evaluation of muscle aging and genetic muscle degeneration. TA form over time, appears in aging in normal murine muscles. TA reduction in injured conditions may be due to the degeneration-regeneration process in muscles, with loss of damaged muscle fibers and formation of new fibers that do not present protein aggregation. These new regenerated fibers do not improve the function capacity of the aged muscle. Here, we present a methodology for labeling and identifying tubular aggregates in muscle fibers and also the standardization of its quantification.

Effects of thyroid hormones in skeletal muscle protein turnover.

Thyroid hormones (THs) are critical regulators of muscle metabolism in both healthy and unhealthy conditions. Acting concurrently as powerful anabolic and catabolic factors, THs are endowed with a vital role in muscle mass maintenance. As a result, thyroid dysfunctions are the leading cause of a wide range of muscle pathologies, globally identified as myopathies. Whether muscle wasting is a common feature in patients with hyperthyroidism and is mainly caused by THs-dependent stimulation of muscle proteolysis, also muscle growth is often associated with hyperthyroid conditions, linked to THs-dependent stimulation of muscle protein synthesis. Noteworthy, also hypothyroid status negatively impacts on muscle physiology, causing muscle weakness and fatigue. Most of these symptoms are due to altered balance between muscle protein synthesis andbreakdown. Thus, a comprehensive understanding of THs-dependent skeletal muscle protein turnover might facilitate the management of physical discomfort or weakness in conditions of thyroid disease. Herein, we describe the molecular mechanisms underlying the THs-dependent alteration of skeletal muscle structure and function associated with muscle atrophy and hypertrophy, thus providing new insights for targeted modulation of skeletal muscle dynamics.

Multimodal three-dimensional characterization of murine skeletal muscle micro-scale elasticity, structure, and composition: Impact of dysferlinopathy, Duchenne muscular dystrophy, and age on three hind-limb muscles

Skeletal muscle tissue function is governed by the mechanical properties and organization of its components, including myofibers, extracellular matrix, and adipose tissue, which can be modified by the onset and progression of many disorders. This study used a novel combination of quantitative micro-elastography and clearing-enhanced three-dimensional (3D) microscopy to assess 3D micro-scale elasticity and micro-architecture of muscles from two muscular dystrophies: dysferlinopathy and Duchenne muscular dystrophy, using male BLA/J and mdx mice, respectively, and their wild-type (WT) controls. We examined three muscles with varying proportions of slow- and fast-twitch myofibers: the soleus (predominantly slow), extensor digitorum longus (EDL; fast), and quadriceps (mixed), from BLA/J and WTBLA/J mice aged 3, 10, and 24 months, and mdx and WTmdx mice aged 10 months. Both dysferlin deficiency and age reduced the elasticity and variability of elasticity of the soleus and quadriceps, but not EDL. Overall, the BLA/J soleus was 20% softer than WT and less mechanically heterogeneous (−14% in standard deviation of elasticity). The BLA/J quadriceps at 24 months was 72% softer than WT and less mechanically heterogeneous (−59% in standard deviation), with substantial adipose tissue accumulation. While mdx muscles did not differ quantitatively from WT, regional heterogeneity was evident in micro-scale elasticity and micro-architecture of quadriceps (e.g., 11.2 kPa in a region with marked pathology vs 3.8 kPa in a less affected area). These results demonstrate differing biomechanical changes in hind-limb muscles of two distinct muscular dystrophies, emphasizing the potential for this novel multimodal technique to identify important differences between various myopathies.

Pathomechanisms of Monoallelic variants in TTN causing skeletal muscle disease.

Pathogenic variants in the titin gene (TTN) are known to cause a wide range of cardiac and musculoskeletal disorders, with skeletal myopathy mostly attributed to biallelic variants. We identified monoallelic truncating variants (TTNtv), splice site or internal deletions in TTN in probands with mild, progressive axial and proximal weakness, with dilated cardiomyopathy frequently developing with age. These variants segregated in an autosomal dominant pattern in 7 out of 8 studied families. We investigated the impact of these variants on mRNA, protein levels, and skeletal muscle structure and function. Results reveal that nonsense-mediated decay likely prevents accumulation of harmful truncated protein in skeletal muscle in patients with TTNtvs. Splice variants and an out-of-frame deletion induce aberrant exon skipping, while an in-frame deletion produces shortened titin with intact N- and C-termini, resulting in disrupted sarcomeric structure. All variant types were associated with genome-wide changes in splicing patterns, which represent a hallmark of disease progression. Lastly, RNA-seq studies revealed that GDF11, a member of the TGF-β superfamily, is upregulated in diseased tissue, indicating that it might be a useful therapeutic target in skeletal muscle titinopathies.

Exploring neuronal mechanisms of osteosarcopenia in older adults.

Until recently, research on the pathogenesis and treatment of osteoporosis and sarcopenia has primarily focused on local and systemic humoral mechanisms, often overlooking neuronal mechanisms. However, there is a growing body of literature on the neuronal regulation of bone and skeletal muscle structure and function, which may provide insights into the pathogenesis of osteosarcopenia. This review aims to integrate these neuronal regulatory mechanisms to form a comprehensive understanding and inspire future research that could uncover novel strategies for preventing and treating osteosarcopenia. Specifically, the review explores the functional adaptation of weight-bearing bone to mechanical loading throughout evolutionary development, from Wolff's law and Frost's mechanostat theory to the mosaic hypothesis, which emphasizes neuronal regulation. The recently introduced bone osteoregulation reflex points to the importance of the osteocytic mechanoreceptive network as a receptor in this neuronal regulation mechanism. Finally, the review focuses on the bone myoregulation reflex, which is known as a mechanism by which bone loading regulates muscle functions neuronally. Considering the ageing-related regressive changes in the nerve fibres that provide both structural and functional regulation in bone and skeletal muscle tissue and the bone and muscle tissues they innervate, it is suggested that neuronal mechanisms might play a central role in explaining osteosarcopenia in older adults.

Constitutive, Muscle-Specific Orai1 Knockout Results in the Incomplete Assembly of Ca2+ Entry Units and a Reduction in the Age-Dependent Formation of Tubular Aggregates.

Store-operated Ca2+ entry (SOCE) is a ubiquitous cellular mechanism that cells use to activate extracellular Ca2+ entry when intracellular Ca2+ stores are depleted. In skeletal muscle, SOCE occurs within Ca2+ entry units (CEUs), intracellular junctions between stacks of SR membranes containing STIM1 and transverse tubules (TTs) containing ORAI1. Gain-of-function mutations in STIM1 and ORAI1 are linked to tubular aggregate (TA) myopathy, a disease characterized by the atypical accumulation of tubes of SR origin. Moreover, SOCE and TAs are increased in the muscles of aged male mice. Here, we assessed the longitudinal effects (from 4-6 months to 10-14 months of age) of constitutive, muscle-specific Orai1 knockout (cOrai1 KO) on skeletal muscle structure, function, and the assembly of TAs and CEUs. The results from these studies indicate that cOrai1 KO mice exhibit a shorter lifespan, reduced body weight, exercise intolerance, decreased muscle-specific force and rate of force production, and an increased number of structurally damaged mitochondria. In addition, electron microscopy analyses revealed (i) the absence of TAs with increasing age and (ii) an increased number of SR stacks without adjacent TTs (i.e., incomplete CEUs) in cOrai1 KO mice. The absence of TAs is consistent with TAs being formed as a result of excessive ORAI1-dependent Ca2+ entry.

The emerging roles of necroptosis in skeletal muscle health and disease.

Necroptosis is a regulated form of cell death with implications in various physiological and pathological processes in multiple tissues. However, the relevant findings from post-mitotic tissues, such as skeletal muscle, are scarce. This review summarizes the potential contributions of necroptosis to skeletal muscle health and diseases. It first discusses the physiological roles of necroptosis in muscle regeneration and development. It then summarizes the contributions of necroptosis to the pathogenesis of multiple muscle diseases, including muscular dystrophies, inflammatory myopathies, cachexia, and neuromuscular disorders. Lastly, it unravels the gaps in our understanding and therapeutic challenges of inhibiting necroptosis as a potential intervention for muscle diseases. Specifically, the findings from the transgenic animal models and the use of pharmacological inhibitors of necroptosis are discussed with relevance to improving the structure and/or function of skeletal muscle in various diseases. Recent developments from experimental animal models and clinical data are presented to discuss the roles of necroptosis in skeletal muscle health and diseases.

Biodegradable conductive IPN in situ cryogels with anisotropic microchannels and sequential delivery of dual-growth factors for skeletal muscle regeneration

Biodegradable and anisotropic cryogels that simulate conductivity and ECM orientation structure of skeletal muscle, and release multiple growth factors, are expected for in situ skeletal muscle tissue engineering. Herein, biodegradable, conductive and anisotropic interpenetrating network (IPN) in situ cryogels are fabricated through Schiff base/acylhydrazone crosslinking via combining unidirectional freezing and cyclic freeze-thaw processes. The cryogels have good anisotropic mechanical properties and oriented microchannel structure, and induce the oriented alignment of myoblasts. The introduction of aniline tetramer enhances the mechanical properties and conductivity of the cryogels. The conductive cryogels significantly improve the proliferation and myogenic differentiation of C2C12 cells during 3D culture. The sequential delivery of insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) can induce migration of human umbilical vein endothelial cells (HUVECs), proliferation of human skin myofibroblasts (HMFB), and myogenic differentiation of C2C12 cells in vitro. In particular, conductive and anisotropic cryogels with dual-growth factors can significantly improve the repair efficiency of volumetric muscle loss (VML) in vivo. This study provides a new strategy to fabricate anisotropic and conductive IPN in situ cryogel biomimetic scaffolds that can encapsulate dual-growth factors and deliver them in time sequence, which significantly promote the efficient repair of VML via an in situ tissue engineering approach.

Skeletal muscle: molecular structure, myogenesis, biological functions, and diseases.

Skeletal muscle is an important motor organ with multinucleated myofibers as its smallest cellular units. Myofibers are formed after undergoing cell differentiation, cell-cell fusion, myonuclei migration, and myofibril crosslinking among other processes and undergo morphological and functional changes or lesions after being stimulated by internal or external factors. The above processes are collectively referred to as myogenesis. After myofibers mature, the function and behavior of skeletal muscle are closely related to the voluntary movement of the body. In this review, we systematically and comprehensively discuss the physiological and pathological processes associated with skeletal muscles from five perspectives: molecule basis, myogenesis, biological function, adaptive changes, and myopathy. In the molecular structure and myogenesis sections, we gave a brief overview, focusing on skeletal muscle-specific fusogens and nuclei-related behaviors including cell-cell fusion and myonuclei localization. Subsequently, we discussed the three biological functions of skeletal muscle (muscle contraction, thermogenesis, and myokines secretion) and its response to stimulation (atrophy, hypertrophy, and regeneration), and finally settled on myopathy. In general, the integration of these contents provides a holistic perspective, which helps to further elucidate the structure, characteristics, and functions of skeletal muscle.

3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights into MFN-2 Mediated Changes.

Age-related atrophy of skeletal muscle, is characterized by loss of mass, strength, endurance, and oxidative capacity during aging. Notably, bioenergetics and protein turnover studies have shown that mitochondria mediate this decline in function. Although exercise has been the only therapy to mitigate sarcopenia, the mechanisms that govern how exercise serves to promote healthy muscle aging are unclear. Mitochondrial aging is associated with decreased mitochondrial capacity, so we sought to investigate how aging affects mitochondrial structure and potential age-related regulators. Specifically, the three-dimensional (3D) mitochondrial structure associated with morphological changes in skeletal muscle during aging requires further elucidation. We hypothesized that aging causes structural remodeling of mitochondrial 3D architecture representative of dysfunction, and this effect is mitigated by exercise. We used serial block-face scanning electron microscopy to image human skeletal tissue samples, followed by manual contour tracing using Amira software for 3D reconstruction and subsequent analysis of mitochondria. We then applied a rigorous in vitro and in vivo exercise regimen during aging. Across 5 human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria we less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.

CISD3/MiNT is required for complex I function, mitochondrial integrity, and skeletal muscle maintenance

Mitochondria play a central role in muscle metabolism and function. A unique family of iron-sulfur proteins, termed CDGSH Iron Sulfur Domain-containing (CISD/NEET) proteins, support mitochondrial function in skeletal muscles. The abundance of these proteins declines during aging leading to muscle degeneration. Although the function of the outer mitochondrial CISD/NEET proteins, CISD1/mitoNEET and CISD2/NAF-1, has been defined in skeletal muscle cells, the role of the inner mitochondrial CISD protein, CISD3/MiNT, is currently unknown. Here, we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne muscular dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscles, as well as their mitochondria, and that CISD3 interacts with, and donates its [2Fe-2S] clusters to, complex I respiratory chain subunit NADH Ubiquinone Oxidoreductase Core Subunit V2 (NDUFV2). Using coevolutionary and structural computational tools, we model a CISD3-NDUFV2 complex with proximal coevolving residue interactions conducive of [2Fe-2S] cluster transfer reactions, placing the clusters of the two proteins 10 to 16 Å apart. Taken together, our findings reveal that CISD3/MiNT is important for supporting the biogenesis and function of complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact different muscle degeneration syndromes, aging, and related conditions.

Ablation of Sam50 is associated with fragmentation and alterations in metabolism in murine and human myotubes.

The sorting and assembly machinery (SAM) Complex is responsible for assembling β-barrel proteins in the mitochondrial membrane. Comprising three subunits, Sam35, Sam37, and Sam50, the SAM complex connects the inner and outer mitochondrial membranes by interacting with the mitochondrial contact site and cristae organizing systemcomplex. Sam50, in particular, stabilizes the mitochondrial intermembrane space bridging (MIB) complex, which is crucial for protein transport, respiratory chain complex assembly, and regulation of cristae integrity. While the role of Sam50 in mitochondrial structure and metabolism in skeletal muscle remains unclear, this study aims to investigate its impact. Serial block-face-scanning electron microscopyand computer-assisted 3D renderings were employed to compare mitochondrial structure and networking in Sam50-deficient myotubes from mice and humans with wild-type (WT) myotubes. Furthermore, autophagosome 3D structure was assessed in human myotubes. Mitochondrial metabolic phenotypes were assessed using Gas Chromatography-Mass Spectrometry-based metabolomics to explore differential changes in WT and Sam50-deficient myotubes. The results revealed increased mitochondrial fragmentation and autophagosome formation in Sam50-deficient myotubes compared to controls. Metabolomic analysis indicated elevated metabolism of propanoate and several amino acids, including ß-Alanine, phenylalanine, and tyrosine, along with increased amino acid and fatty acid metabolism in Sam50-deficient myotubes. Furthermore, impairment of oxidative capacity was observed upon Sam50 ablation in both murine and human myotubes, as measured with the XF24 Seahorse Analyzer. Collectively, these findings support the critical role of Sam50 in establishing and maintaining mitochondrial integrity, cristae structure, and mitochondrial metabolism. By elucidating the impact of Sam50-deficiency, this study enhances our understanding of mitochondrial function in skeletal muscle.

Biomaterials-Based Technologies in Skeletal Muscle Tissue Engineering.

For many clinically prevalent severe injuries, the inherent regenerative capacity of skeletal muscle remains inadequate. Skeletal muscle tissue engineering (SMTE) seeks to meet this clinical demand. With continuous progress in biomedicine and related technologies including micro/nanotechnology and 3D printing, numerous studies have uncovered various intrinsic mechanisms regulating skeletal muscle regeneration and developed tailored biomaterial systems based on these understandings. Here, the skeletal muscle structure and regeneration process are discussed and the diverse biomaterial systems derived from various technologies are explored in detail. Biomaterials serve not merely as local niches for cell growth, but also as scaffolds endowed with structural or physicochemical properties that provide tissue regenerative cues such as topographical, electrical, and mechanical signals. They can also act as delivery systems for stem cells and bioactive molecules that have been shown as key participants in endogenous repair cascades. To achieve bench-to-bedside translation, the typical effect enabled by biomaterial systems and the potential underlying molecular mechanisms are also summarized. Insights into the roles of biomaterials in SMTE from cellular and molecular perspectives are provided. Finally, perspectives on the advancement of SMTE are provided, for which gene therapy, exosomes, and hybrid biomaterials may hold promise to make important contributions.

Roles of natural products on myokine expression and secretion in skeletal muscle atrophy

Skeletal muscles serve both in movement and as endocrine organs. Myokines secreted by skeletal muscles activate biological functions within muscles and throughout the body via autocrine, paracrine, and/or endocrine pathways. Skeletal muscle atrophy can influence myokine expression and secretion, while myokines can impact the structure and function of skeletal muscles. Regulating the expression and secretion of myokines through the pharmacological approach is a strategy for alleviating skeletal muscle atrophy. Natural products possess complex structures and chemical properties. Previous studies have demonstrated that various natural products exert beneficial effects on skeletal muscle atrophy. This article reviewed the regulatory effects of natural products on myokines and summarized the research progress on skeletal muscle atrophy associated with myokine regulation. The focus is on how small-molecule natural products affect the regulation of interleukin 6 (IL-6), irisin, myostatin, IGF-1, and FGF-21 expression. We contend that the development of small-molecule natural products targeting the regulation of myokines holds promise in combating skeletal muscle atrophy.

Muscle Psn gene combined with exercise contribute to healthy aging of skeletal muscle and lifespan by adaptively regulating Sirt1/PGC-1α and arm pathway.

The Presenilin (Psn) gene is closely related to aging, but it is still unclear the role of Psn genes in skeletal muscle. Here, the Psn-UAS/Mhc-GAL4 system in Drosophila was used to regulate muscle Psn overexpression(MPO) and muscle Psn knockdown(MPK). Drosophila were subjected to endurance exercise from 4 weeks to 5 weeks old. The results showed that MPO and exercise significantly increased climbing speed, climbing endurance, lifespan, muscle SOD activity, Psn expression, Sirt1 expression, PGC-1α expression, and armadillo (arm) expression in aged Drosophila, and they significantly decreased muscle malondialdehyde levels. Interestingly, when the Psn gene is knockdown by 0.78 times, the PGC-1α expression and arm expression were also down-regulated, but the exercise capacity and lifespan were increased. Furthermore, exercise combined with MPO further improved the exercise capacity and lifespan. MPK combined with exercise further improves the exercise capacity and lifespan. Thus, current results confirmed that the muscle Psn gene was a vital gene that contributed to the healthy aging of skeletal muscle since whether it was overexpressed or knocked down, the aging progress of skeletal muscle structure and function was slowed down by regulating the activity homeostasis of Sirt1/PGC-1α pathway and Psn/arm pathway. Exercise enhanced the function of the Psn gene to delay skeletal muscle aging by up regulating the activity of the Sirt1/PGC-1α pathway and Psn/arm pathway.

Evaluating the effects of hormone therapy termination on skeletal muscle and physical independence in postmenopausal women.

In women, the age-related decline in skeletal muscle structure and function is accelerated after menopause, which implicates the role of decreased circulating estrogen levels. Indeed, boosting estrogen, by means of postmenopausal hormone therapy (HT), generally proves beneficial to skeletal muscle. The evidence regarding whether these benefits persist even after cessation of HT is limited, nor is it clear how physical behavior (PB) impacts on benefits. Hence, this exploratory study focused on the interplay between HT administration/cessation, PB and in vivo skeletal muscle structure and function. Fifty healthy women (≥60 y) were included; 19 had an HT administration history (≥9 mo, with now ~8-y hiatus in treatment) and 31 no such history. On seven continuous days, PB data were collected using triaxial accelerometry and analyzed using compositional data analysis. Gastrocnemius medialis muscle volume, architecture, and function were determined using ultrasonography, electromyography, dual x-ray absorptiometry, and dynamometry. Current serum estradiol levels were measured using ELISA. Only fascicle length and duration of HT administration were positively associated. With respect to PB levels, we found a pattern suggesting greater vitality (higher physical activity and lower sedentarism) in previous HT users, compared with nonusers, despite the two groups currently no longer exhibiting significantly different levels of circulating estradiol. After an 8-year hiatus in treatment, HT provides limited advantages in gastrocnemius medialis muscle properties. Interestingly, it perhaps enhances vitality despite prolonged cessation, which in the longer term would facilitate greater physical independence, especially considering the association of sedentary behavior with greater frailty.