Skeletal Muscle Disease Research Articles

Sporadic Inclusion Body Myositis

Sporadic inclusion body myositis (sIBM) is an intractable and progressive skeletal muscle disease of unknown etiology. Muscle biopsy typically reveals endomysial inflammation, invasion of mononuclear cells into non-necrotic fibers, and rimmed vacuoles, suggesting that inflammation and degeneration co-exist in the pathomechanism. According to a nationwide survey conducted by a research team of the Ministry of Health, Labor, and Welfare, the number of patients is increasing in Japan as well. The clinical progression shows a slow and chronic deterioration. sIBM is usually diagnosed five years after onset. Muscle weakness and atrophy in the quadriceps, wrist flexors, and finger flexors are typical neurological findings of sIBM. Dysphagia and asymmetric weakness are often found. Serum creatine kinase is usually below 2,000 IU/L. sIBM is generally refractory to current therapy, such as steroids or immunosuppressants. Understanding the pathomechanism of sIBM is crucial for developing effective therapeutic strategies.

The Influence of a Genetic Variant in CCDC78 on LMNA-Associated Skeletal Muscle Disease.

Mutations in the LMNA gene-encoding A-type lamins can cause Limb-Girdle muscular dystrophy Type 1B (LGMD1B). This disease presents with weakness and wasting of the proximal skeletal muscles and has a variable age of onset and disease severity. This variability has been attributed to genetic background differences among individuals; however, such variants have not been well characterized. To identify such variants, we investigated a multigeneration family in which affected individuals are diagnosed with LGMD1B. The primary genetic cause of LGMD1B in this family is a dominant mutation that activates a cryptic splice site, leading to a five-nucleotide deletion in the mature mRNA. This results in a frame shift and a premature stop in translation. Skeletal muscle biopsies from the family members showed dystrophic features of variable severity, with the muscle fibers of some family members possessing cores, regions of sarcomeric disruption, and a paucity of mitochondria, not commonly associated with LGMD1B. Using whole genome sequencing (WGS), we identified 21 DNA sequence variants that segregate with the family members possessing more profound dystrophic features and muscle cores. These include a relatively common variant in coiled-coil domain containing protein 78 (CCDC78). This variant was given priority because another mutation in CCDC78 causes autosomal dominant centronuclear myopathy-4, which causes cores in addition to centrally positioned nuclei. Therefore, we analyzed muscle biopsies from family members and discovered that those with both the LMNA mutation and the CCDC78 variant contain muscle cores that accumulated both CCDC78 and RyR1. Muscle cores containing mislocalized CCDC78 and RyR1 were absent in the less profoundly affected family members possessing only the LMNA mutation. Taken together, our findings suggest that a relatively common variant in CCDC78 can impart profound muscle pathology in combination with a LMNA mutation and accounts for variability in skeletal muscle disease phenotypes.

Cell-type specific effects of mineralocorticoid receptor gene expression suggest intercellular communication regulating fibrosis in skeletal muscle disease.

Introduction: Duchenne muscular dystrophy (DMD) is a fatal striated muscle degenerative disease. DMD is caused by loss of dystrophin protein, which results in sarcolemmal instability and cycles of myofiber degeneration and regeneration. Pathology is exacerbated by overactivation of infiltrating immune cells and fibroblasts, which leads to chronic inflammation and fibrosis. Mineralocorticoid receptors (MR), a type of nuclear steroid hormone receptors, are potential therapeutic targets for DMD. MR antagonists show clinical efficacy on DMD cardiomyopathy and preclinical efficacy on skeletal muscle in DMD models. Methods: We have previously generated myofiber and myeloid MR knockout mouse models to dissect cell-specific functions of MR within dystrophic muscles. Here, we compared skeletal muscle gene expression from both knockouts to further define cell-type specific signaling downstream from MR. Results: Myeloid MR knockout increased proinflammatory and profibrotic signaling, including numerous myofibroblast signature genes. Tenascin C was the most highly upregulated fibrotic gene in myeloid MR-knockout skeletal muscle and is a component of fibrosis in dystrophic skeletal muscle. Surprisingly, lysyl oxidase (Lox), canonically a collagen crosslinker, was increased in both MR knockouts, but did not localize to fibrotic regions of skeletal muscle. Lox localized within myofibers, including only a region of quadriceps muscles. Lysyl oxidase like 1 (Loxl1), another Lox family member, was increased only in myeloid MR knockout muscle and localized specifically to fibrotic regions. Discussion: This study suggests that MR signaling in the dystrophic muscle microenvironment involves communication between contributing cell types and modulates inflammatory and fibrotic pathways in muscle disease.

Differential metabolic secretion between muscular dystrophy mouse-derived spindle cell sarcomas and rhabdomyosarcomas drives tumor type development.

The dystrophin gene (Dmd) is recognized for its significance in Duchenne muscular dystrophy (DMD), a lethal and progressive skeletal muscle disease. Some patients with DMD and model mice with muscular dystrophy (mdx) spontaneously develop various types of tumors, among which rhabdomyosarcoma (RMS) is the most prominent. By contrast, spindle cell sarcoma (SCS) has rarely been reported in patients or mdx mice. In this study, we aimed to use metabolomics to better understand the rarity of SCS development in mdx mice. Gas chromatography-mass spectrometry was used to compare the metabolic profiles of spontaneously developed SCS and RMS tumors from mdx mice, and metabolite supplementation assays and silencing experiments were used to assess the effects of metabolic differences in SCS tumor-derived cells. The levels of 75 metabolites exhibited differences between RMS and SCS, 25 of which were significantly altered. Further characterization revealed downregulation of nonessential amino acids, including alanine, in SCS tumors. Alanine supplementation enhanced the growth, epithelial mesenchymal transition, and invasion of SCS cells. Reduction of intracellular alanine via knockdown of the alanine transporter Slc1a5 reduced the growth of SCS cells. Lower metabolite secretion and reduced proliferation of SCS tumors may explain the lower detection rate of SCS in mdx mice. Targeting of alanine depletion pathways may have potential as a novel treatment strategy.NEW & NOTEWORTHY To the best of our knowledge, SCS has rarely been identified in patients with DMD or mdx mice. We observed that RMS and SCS tumors that spontaneously developed from mdx mice with the same Dmd genetic background exhibited differences in metabolic secretion. We proposed that, in addition to dystrophin deficiency, the levels of secreted metabolites may play a role in the determination of tumor-type development in a Dmd-deficient background.

Temporal regulation of the Mediator complex during muscle proliferation, differentiation, regeneration, aging, and disease.

Genesis of skeletal muscle relies on the differentiation and fusion of mono-nucleated muscle progenitor cells into the multi-nucleated muscle fiber syncytium. The temporally-controlled cellular and morphogenetic changes underlying this process are initiated by a series of highly coordinated transcription programs. At the core, the myogenic differentiation cascade is driven by muscle-specific transcription factors, i.e., the Myogenic Regulatory Factors (MRFs). Despite extensive knowledge on the function of individual MRFs, very little is known about how they are coordinated. Ultimately, highly specific coordination of these transcription programs is critical for their masterfully timed transitions, which in turn facilitates the intricate generation of skeletal muscle fibers from a naïve pool of progenitor cells. The Mediator complex links basal transcriptional machinery and transcription factors to regulate transcription and could be the integral component that coordinates transcription factor function during muscle differentiation, growth, and maturation. In this study, we systematically deciphered the changes in Mediator complex subunit expression in skeletal muscle development, regeneration, aging, and disease. We incorporated our in vitro and in vivo experimental results with analysis of publicly available RNA-seq and single nuclei RNA-seq datasets and uncovered the regulation of Mediator subunits in different physiological and temporal contexts. Our experimental results revealed that Mediator subunit expression during myogenesis is highly dynamic. We also discovered unique temporal patterns of Mediator expression in muscle stem cells after injury and during the early regeneration period, suggesting that Mediator subunits may have unique contributions to directing muscle stem cell fate. Although we observed few changes in Mediator subunit expression in aging muscles compared to younger muscles, we uncovered extensive heterogeneity of Mediator subunit expression in dystrophic muscle nuclei, characteristic of chronic muscle degeneration and regeneration cycles. Taken together, our study provides a glimpse of the complex regulation of Mediator subunit expression in the skeletal muscle cell lineage and serves as a springboard for mechanistic studies into the function of individual Mediator subunits in skeletal muscle.

Prognostic and functional importance of both overt and subclinical left ventricular systolic dysfunction in systemic sclerosis

ObjectivesTo quantify the frequency and clinical implications of systemic sclerosis (SSc)-associated left ventricular function (LV) impairment. MethodsAustralian Scleroderma Cohort Study participants meeting ACR/EULAR criteria for SSc with ≥1 echocardiographic LVEF measurement were included. Overt LV dysfunction was indicated by reduced LV ejection fraction (LVEF) and subclinical LV dysfunction was measured using impaired LV global longitudinal strain (LV-GLS>-16 %). Those with secondary causes of LV dysfunction (myocardial ischaemia, valvulopathy and pulmonary arterial hypertension) were excluded. Chi-squared tests, two-sample t-tests or Wilcoxon rank-sum tests were used for between-group comparison as appropriate. Generalised estimating equations(GEE) were used to model longitudinal data. Kaplan-Meier and Cox proportional hazard models were used for survival analyses. ResultsOf 1141 participants with no co-morbid cardiac disease, 2.4 % ever recorded a LVEF<50 %, while only 0.6 % ever recorded a LVEF≤40 %. LV-GLS data were available for 90 % of participants at one centre (n = 218). Impaired LV-GLS was detected in 21 % despite LVEF≥50 %. Those with a LVEF<50 % were more frequently male (p = 0.01) with dcSSc (p < 0.01), higher inflammatory markers (p < 0.02) and skeletal muscle disease (p < 0.05). In multivariable analyses, recording a LVEF<50 % was associated with increased mortality (HR2.3, 95 %CI1.0–4.8, p = 0.04). Impaired LV-GLS was also associated with poorer survival in univariable analyses (HR3.4, 95 %CI1.0–11.8, p = 0.05). Those with a LVEF<50 % more frequently recorded WHO Class III/IV dyspnoea (OR3.5, 95 %CI1.6–7.7, p < 0.01), with shorter six-minute walk distance (p = 0.01), higher Health Assessment Questionnaire-Disability Index scores (p < 0.01) and lower Short Form-36 Physical Component Summary scores (p = 0.02). Increased dyspnoea (WHO Class III/IV dyspnoea; OR3.6, 95 %CI1.4–9.2, p < 0.01) was also seen in those with impaired LV-GLS. ConclusionsBoth overt and subclinical SSc-associated LV dysfunction are associated with worse survival and impaired physical function. The frequency of abnormal LV-GLS in those with consistently normal LVEF suggests an under-appreciated burden of subtle LV systolic dysfunction in SSc that has a significant impact on patient symptomatology.

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.

식물 추출물 혼합 분말이 C2C12 세포 내 분화 및 산화적 스트레스 유발 세포사멸 조절에 미치는 효과

This study evaluated the differentiation and protective effects of mixed plant-extract powder in C2C12 muscle cells. Cells were differentiated into myotubes in 2% horse serum (HS)-containing medium with mixed plant-extract powder (MPEP) for 6 days. Treatment with MPEP increased the expression of myogenin and myosin heavy chain (MHC) protein in cells compared with non-treated cells. Differentiated cells were pretreated with MPEP, and hydrogen peroxide (H2O2). Our results revealed that treatment with MPEP before H2O2 treatment increased cell viability and decreased H2O2-induced lactate dehydrogenase (LDH) and creatine kinase (CK). In addition, MPEP attenuated H2O2-induced upregulation of Bax, downregulation of Bcl-2, and activation of caspase-9 and -3. These results suggest the MPEP can stimulate C2C12 muscle cell differentiation into myotubes and observe the protective effect of mixed plant-extract powder against muscle oxidative stress. In conclusion, MPEP may be useful as a prevention and treatment material for skeletal muscle disease caused by age-related diseases.

Analysis of related factors for sarco-osteoporosis in middle-aged and elderly inpatients and development and validation of a nomogram

BackgroundSarco-osteoporosis is a skeletal muscle disease associated with aging and complex pathological factors. At present, there are few studies on the analysis of its related factors, and a nomogram to estimate the risk of sarco-osteoporosis in middle-aged and elderly patients is not available.MethodsA total of 386 patients admitted to our hospital from October 2021 to October 2022 were collected, and the general demographic data and clinical data of the patients were collected.386 subjects were enrolled in the study and randomly divided into training set and validation set at a ratio of 7:3. In the training set, the Least absolute shrinkage and selection operator(LASSO)regression technique was used to select the optimal predictive features, and multivariate logistic regression was used to screen the factors associated with sarco-osteoporosis, and a nomogram was constructed using meaningful variables from multivariate analysis. The performance of the nomograms was assessed and validated by Area Under Curve (AUC) and calibration curves.ResultsThere were no significant differences in baseline characteristic of individuals in training set and validation set, six variables with non-zero coefficients were screened based on LASSO regression in the training set. Multivariate logistic regression analysis showed that the related factors for sarco-osteoporosis in middle-aged and elderly inpatients included age (OR = 1.08, 95%CI 1.03 ∼ 1.14), regular exercise (OR = 0.29, 95%CI 0.15 ∼ 0.56), albumin (OR = 0.9, 95%CI 0.82 ∼ 0.98), height (OR = 0.93, 95%CI 0.88 ∼ 0.99) and lean mass index (OR = 0.66, 95%CI 0.52 ∼ 0.85), and a nomogram was constructed based on the above factors. AUC of nomogram were 0.868(95%CI 0.825 ∼ 0.912) in the training set and 0.737(95%CI 0.646 ∼ 0.828) in the validation set. Calibration curve analysis showed that the predicted probability of sarco-osteoporosis had high consistency with the actual probability, and the absolute error of the training set and verification set was 0.018 and 0.03, respectively.ConclusionsOur research showed that the occurrence of sarco-osteoporosis was associated with age, regular exercise, albumin, height and lean mass index, and we have developed a nomogram that can be effectively used in the preliminary and in-depth risk prediction of sarco-osteoporosis in middle-aged and elderly hospitalized patients.

Imaging spectrum of atraumatic muscle disorders: a radiologist's guide.

Atraumatic muscle disorders comprise a very wide range of skeletal muscle diseases, including metabolic, inflammatory, autoimmune, infectious, ischemic, and neoplastic involvement of the muscles. Therefore, one must take clinical and laboratory data into consideration to elucidate the differential diagnoses, as well as the distribution of the muscle compromise along the body-whether isolated or distributed along the body in a symmetric or asymmetrical fashion. Assessment of muscular disorders often requires imaging investigation before image-guided biopsy or more invasive procedures; therefore, radiologists should understand the advantages and limitations of imaging methods for proper lesion evaluation and be aware of the imaging features of such disorders, thus contributing to proper decision-making and good patient outcomes. In this review, we propose a systematic approach for the assessment of muscle disorders based on their main imaging presentation, dividing them into patterns that can be easily recognized.

An Intronic Heterozygous SYNE2 Splice Site Mutation: A Rare Cause for Myalgia and hyperCKemia?

SYNE2 mutations have been associated with skeletal and cardiac muscle diseases, including Emery-Dreifuss muscular dystrophy (EDMD). Here, we present a 70-year-old male patient with muscle pain and elevated serum creatine kinase levels in whom whole-exome sequencing revealed a novel heterozygous SYNE2 splice site mutation (NM_182914.3:c.15306+2T&gt;G). This mutation is likely to result in the loss of the donor splice site in intron 82. While a diagnostic muscle biopsy showed unspecific myopathological findings, immunofluorescence analyses of skeletal muscle and dermal cells derived from the patient showed nuclear shape alterations when compared to control cells. In addition, a significantly reduced nesprin-2 giant protein localisation to the nuclear envelope was observed in patient-derived dermal fibroblasts. Our findings imply that the novel heterozygous SYNE2 mutation results in a monoallelic splicing defect of nesprin-2, thereby leading to a rare cause of myalgia and hyperCKemia.

Mitochondrial-Targeted Metal-Phenolic Nanoparticles to Attenuate Intervertebral Disc Degeneration: Alleviating Oxidative Stress and Mitochondrial Dysfunction.

As intervertebral disc degeneration (IVDD) proceeds, the dysfunctional mitochondria disrupt the viability of nucleus pulposus cells, initiating the degradation of the extracellular matrix. To date, there is a lack of effective therapies targeting the mitochondria of nucleus pulposus cells. Here, we synthesized polygallic acid-manganese (PGA-Mn) nanoparticles via self-assembly polymerization of gallic acid in an aqueous medium and introduced a mitochondrial targeting peptide (TP04) onto the nanoparticles using a Schiff base linkage, resulting in PGA-Mn-TP04 nanoparticles. With a size smaller than 50 nm, PGA-Mn-TP04 possesses pH-buffering capacity, avoiding lysosomal confinement and selectively accumulating within mitochondria through electrostatic interactions. The rapid electron exchange between manganese ions and gallic acid enhances the redox capability of PGA-Mn-TP04, effectively reducing mitochondrial damage caused by mitochondrial reactive oxygen species. Moreover, PGA-Mn-TP04 restores mitochondrial function by facilitating the fusion of mitochondria and minimizing their fission, thereby sustaining the vitality of nucleus pulposus cells. In the rat IVDD model, PGA-Mn-TP04 maintained intervertebral disc height and nucleus pulposus tissue hydration. It offers a nonoperative treatment approach for IVDD and other skeletal muscle diseases resulting from mitochondrial dysfunction, presenting an alternative to traditional surgical interventions.

Association between oxidative balance score and sarcopenia in older adults

Sarcopenia is a progressive skeletal muscle disease in which oxidative stress has been proposed as one of the primary markers. The oxidative balance score (OBS) represents the oxidative balance of a person's dietary pattern using the merged intake of anti-oxidants and pro-oxidants. Therefore, the present study assessed the association between OBS and sarcopenia in Iranian older adults. In the current study, 80 people with sarcopenia and 80 without it were considered the case and control groups, respectively. All controls were matched by sex with cases. To confirm sarcopenia, skeletal muscle mass index (SMI), handgrip strength (HGS) measurement, and gait speed were used. Also, body composition was measured by bioelectrical impedance analysis (BIA). A valid and reliable food frequency questionnaire (FFQ) was used to assess all participants' dietary intake of pro-oxidants and anti-oxidants. Conditional logistic regression was applied to assess the association between OBS and sarcopenia. In the bivariate model, we observed lower odds of sarcopenia in the second and last tertile of OBS in comparison to the first tertile (T) (T2 – odds ratio (OR) = 0.414, 95% confidence interval (CI) : 0.186–0.918 and T3 – OR = 0.101, 95% CI: 0.041–0.248). After adjusting for potential confounders, the association was not significant in second and last tertile of OBS in comparision to the first one. The present study's findings demonstrated that overcoming exposure to anti-oxidants over pro-oxidants, as illustrated by a higher OBS, is not related to lower odds of sarcopenia in older adults.

Collagen VI Deficiency Impairs Tendon Fibroblasts Mechanoresponse in Ullrich Congenital Muscular Dystrophy.

The pericellular matrix (PCM) is a specialized extracellular matrix that surrounds cells. Interactions with the PCM enable the cells to sense and respond to mechanical signals, triggering a proper adaptive response. Collagen VI is a component of muscle and tendon PCM. Mutations in collagen VI genes cause a distinctive group of inherited skeletal muscle diseases, and Ullrich congenital muscular dystrophy (UCMD) is the most severe form. In addition to muscle weakness, UCMD patients show structural and functional changes of the tendon PCM. In this study, we investigated whether PCM alterations due to collagen VI mutations affect the response of tendon fibroblasts to mechanical stimulation. By taking advantage of human tendon cultures obtained from unaffected donors and from UCMD patients, we analyzed the morphological and functional properties of cellular mechanosensors. We found that the length of the primary cilia of UCMD cells was longer than that of controls. Unlike controls, in UCMD cells, both cilia prevalence and length were not recovered after mechanical stimulation. Accordingly, under the same experimental conditions, the activation of the Hedgehog signaling pathway, which is related to cilia activity, was impaired in UCMD cells. Finally, UCMD tendon cells exposed to mechanical stimuli showed altered focal adhesions, as well as impaired activation of Akt, ERK1/2, p38MAPK, and mechanoresponsive genes downstream of YAP. By exploring the response to mechanical stimulation, for the first time, our findings uncover novel unreported mechanistic aspects of the physiopathology of UCMD-derived tendon fibroblasts and point at a role for collagen VI in the modulation of mechanotransduction in tendons.

Diabetes Mellitus Should Be Considered While Analysing Sarcopenia-Related Biomarkers.

Sarcopenia is a chronic, progressive skeletal muscle disease characterised by low muscle strength and quantity or quality, leading to low physical performance. Patients with type 2 diabetes mellitus (T2DM) are more at risk of sarcopenia than euglycemic individuals. Because of several shared pathways between the two diseases, sarcopenia is also a risk factor for developing T2DM in older patients. Various biomarkers are under investigation as potentially valuable for sarcopenia diagnosis and treatment monitoring. Biomarkers related to sarcopenia can be divided into markers evaluating musculoskeletal status (biomarkers specific to muscle mass, markers of the neuromuscular junction, or myokines) and markers assuming causal factors (adipokines, hormones, and inflammatory markers). This paper reviews the current knowledge about how diabetes and T2DM complications affect potential sarcopenia biomarker concentrations. This review includes markers recently proposed by the expert group of the European Society for the Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) as those that may currently be useful in phase II and III clinical trials of sarcopenia: myostatin (MSTN); follistatin (FST); irisin; brain-derived neurotrophic factor (BDNF); procollagen type III N-terminal peptide (PIIINP; P3NP); sarcopenia index (serum creatinine to serum cystatin C ratio); adiponectin; leptin; insulin-like growth factor-1 (IGF-1); dehydroepiandrosterone sulphate (DHEAS); C-reactive protein (CRP); interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). A better understanding of factors influencing these biomarkers' levels, including diabetes and diabetic complications, may lead to designing future studies and implementing results in clinical practice.

Chloroquine decreases cardiac fibrosis and improves cardiac function in a mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD), a severe degenerative skeletal and cardiac muscle disease, has a poor prognosis, and no curative treatments are available. Because decreased autophagy has been reported to contribute to skeletal muscle degeneration, therapies targeting autophagy are expected to improve skeletal muscle hypofunction. However, the role of this regulatory mechanism has not been evaluated clearly in DMD cardiomyocytes. In this present study, we evaluated myocardial fibrosis and its mechanism in mdx mice, a model of DMD, and also evaluated changes in cardiac function. As assessed by LC3 immunohistochemistry, a small number of autophagosomes were detected in cardiomyocytes of both mdx mice and control wild-type (WT) mice. The number of autophagosomes was significantly enhanced by 4 weeks of isoproterenol-induced cardiac stress in cardiomyocytes of mdx but not WT mice. Simultaneously, isoproterenol increased cardiomyocyte fibrosis in mdx but not WT mice. Administration of chloroquine significantly decreased cardiomyocyte fibrosis in mdx mice, even after isoproterenol treatment. Left ventricle size and function were evaluated by echocardiography. Left ventricular contraction was decreased in mdx mice after isoproterenol treatment compared with control mice, which was alleviated by chloroquine administration. Heart failure in DMD patients is possibly treated with chloroquine, and the mechanism probably involves chloroquine's anti-inflammatory effects.

Cellular interactions and microenvironment dynamics in skeletal muscle regeneration and disease.

Skeletal muscle regeneration relies on the intricate interplay of various cell populations within the muscle niche-an environment crucial for regulating the behavior of muscle stem cells (MuSCs) and ensuring postnatal tissue maintenance and regeneration. This review delves into the dynamic interactions among key players of this process, including MuSCs, macrophages (MPs), fibro-adipogenic progenitors (FAPs), endothelial cells (ECs), and pericytes (PCs), each assuming pivotal roles in orchestrating homeostasis and regeneration. Dysfunctions in these interactions can lead not only to pathological conditions but also exacerbate muscular dystrophies. The exploration of cellular and molecular crosstalk among these populations in both physiological and dystrophic conditions provides insights into the multifaceted communication networks governing muscle regeneration. Furthermore, this review discusses emerging strategies to modulate the muscle-regenerating niche, presenting a comprehensive overview of current understanding and innovative approaches.

Exploring mechanisms of insulin action and strategies to treat diabetes.

Insulin is a hormone that positively regulates anabolism and cell growth, whereas diabetes mellitus is a disease characterized by hyperglycemia associated with impaired insulin action. My colleagues and I have elucidated multifaceted insulin action in various tissues mainly by means of model mice. In the liver, insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis comorbid with diabetes. Not only the liver but also the proximal tubules of the kidney are important in the regulation of gluconeogenesis, and we revealed that insulin suppresses gluconeogenesis in accordance with absorbed glucose in the latter tissue. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease of skeletal muscle, but also to osteopenia and shorter longevity. Aging is regulated by adipokines as well, and it should be considered that aging could be accelerated by 'imbalanced adipokines' in patients with a genetic background of progeria. Moreover, we reported the effects of intensive multifactorial intervention on diabetic vascular complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, and the results of subsequent sub-analyses of renal events and fracture events. Various approaches of research enable us of endocrinologists to elucidate the physiology of hormone signaling, the mechanisms underlying the development of endocrine diseases, and the appropriate treatment measures. These approaches also raise fundamental questions, but addressing them in an appropriate manner will surely contribute to the further development of endocrinology.

Sarcopenia as a non-motor symptom of Parkinson's disease

Sarcopenia is a progressive generalized skeletal muscle disease that is accompanied by an accelerated loss of muscle mass and function, affecting the quality of life and the ability to perform self-care. The prevalence of sarcopenia in the world today ranges from 10 to 25%, which represents a certain danger as it is a prognostic factor for possible injury and increased disability in the elderly population. Sarcopenia often accompanies a large number of different diseases, including neurodegenerative ones, so it is actively studied in this category of patients, for example, as one of the early symptoms of Parkinson's disease (PD). PD and sarcopenia have overlapping pathophysiological mechanisms of muscle fiber loss: inflammation, muscle autophagy, oxidative stress and apoptosis. Loss of muscle mass due to malnutrition is common in PD. According to some studies, the prevalence of sarcopenia in PD varies from 6 to 55.8%; weakness and sarcopenia are more common in patients with PD than in society as a whole, which is associated with an unfavorable course of the disease. The presence of both diseases simultaneously in one patient can impose certain restrictions on the treatment of the patient, worsen his physical and mental condition, which determines the need for early detection of sarcopenia in patients with PD.

Unraveling the causes of sarcopenia: Roles of neuromuscular junction impairment and mitochondrial dysfunction.

Sarcopenia is a systemic skeletal muscle disease characterized by a decline in skeletal muscle mass and function. Originally defined as an age-associated condition, sarcopenia presently also encompasses muscular atrophy due to various pathological factors, such as intensive care unit-acquired weakness, inactivity, and malnutrition. The exact pathogenesis of sarcopenia is still unknown; herein, we review the pathological roles of the neuromuscular junction and mitochondria in this condition. Sarcopenia is caused by complex and interdependent pathophysiological mechanisms, including aging, neuromuscular junction impairment, mitochondrial dysfunction, insulin resistance, lipotoxicity, endocrine factors, oxidative stress, and inflammation. Among these, neuromuscular junction instability and mitochondrial dysfunction are particularly significant. Dysfunction in neuromuscular junction can lead to muscle weakness or paralysis. Mitochondria, which are plentiful in neurons and muscle fibers, play an important role in neuromuscular junction transmission. Therefore, impairments in both mitochondria and neuromuscular junction may be one of the key pathophysiological mechanisms leading to sarcopenia. Moreover, this article explores the structural and functional alterations in the neuromuscular junction and mitochondria in sarcopenia, suggesting that a deeper understanding of these changes could provide valuable insights for the prevention or treatment of sarcopenia.