Search

Aims: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease that affects the hepatic bile ducts, leading to hepatic inflammation and fibrosis. PSC can also impact skeletal muscle through the muscle-liver axis, resulting in sarcopenia, a complication characterized by a generalized loss of muscle mass and strength. The underlying mechanisms and therapy of PSC-induced sarcopenia are not well understood, but one potential regulator is the transcription factor forkhead box protein O1 (FOXO1), which is involved in the ubiquitin proteasome system. Thus, the aim of this study is to assess the pharmacological potential of FOXO1 inhibition for treating PSC-induced sarcopenia., Materials and Methods: To establish diet-induced PSC model, we provided mice with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 4 weeks. Mice were intramuscularly injected with AS1842856 (AS), a FOXO1 inhibitor, at a dose of 3.5 mg/kg twice a week for last two weeks. C2C12 myotubes with cholic acid (CA) or deoxycholic acid (DCA) were treated with AS., Key Findings: We observed a decrease in muscle size and performance in DDC-fed mice with upregulated expression of FOXO1 and E3 ligases such as ATROGIN1 and MuRF1. We found that myotube diameter and MyHC protein level were decreased by CA or DCA in C2C12 myotubes, but treatment of AS reversed these reductions. We observed that intramuscular injection of AS effectively mitigates DDC diet-induced sarcopenia in a rodent PSC model., Significance: Our study suggests that a FOXO1 inhibitor could be a potential leading therapeutic drug for relieving PSC-induced sarcopenia., Competing Interests: Declaration of competing interest The authors declare that there are no conflict of interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Heme serves as a prosthetic group in hemoproteins, including subunits of the mammalian mitochondrial electron transfer chain. The first enzyme in vertebrate heme biosynthesis, 5-aminolevulinic acid synthase 1 (ALAS1), is ubiquitously expressed and essential for producing 5-aminolevulinic acid (ALA). We previously showed that Alas1 heterozygous mice at 20-35 weeks (aged-A1 +/- s) manifested impaired glucose metabolism, mitochondrial malformation in skeletal muscle, and reduced exercise tolerance, potentially linked to autophagy dysfunction. In this study, we investigated autophagy in A1 +/- s and a sarcopenic phenotype in A1 +/- s at 75-95 weeks (senile-A1 +/- s). Senile-A1 +/- s exhibited significantly reduced body and gastrocnemius muscle weight, and muscle strength, indicating an accelerated sarcopenic phenotype. Decreases in total LC3 and LC3-II protein and Map1lc3a mRNA levels were observed in aged-A1 +/- s under fasting conditions and in Alas1 knockdown myocyte-differentiated C2C12 cells (A1KD-C2C12s) cultured in high- or low-glucose medium. ALA treatment largely reversed these declines. Reduced AMP-activated protein kinase (AMPK) signaling was associated with decreased autophagy in aged-A1 +/- s and A1KD-C2C12s. AMPK modulation using AICAR (activator) and dorsomorphin (inhibitor) affected LC3 protein levels in an AMPK-dependent manner. Our findings suggest that heme deficiency contributes to accelerated sarcopenia-like defects and reduced autophagy in skeletal muscle, primarily due to decreased AMPK signaling., (© 2024. The Author(s).)

Sesamol is a major bioactive component extracted from sesame seeds and has various medicinal properties. However, the effects of sesamol on sarcopenia associated with aging and obesity remains unclear. Therefore, the protective effects and underlying mechanisms of sesamol on sarcopenia was evaluated in aged and obese C57BL/6 J male mouse models fed a high fat diet and C2C12 myotubes co-treated with D-gal and PA in this study. Our in vivo data showed that sesamol activated AKT/mTOR/FoxO1 signal pathway, and then upregulated p-p70S6K and p-4EBP1 to promote myoprotein synthesis, and downregulated Atrogin-1 and MuRF1 to inhibit myoprotein degradation, thus ameliorating sarcopenia related to aging and obesity. Furthermore, our in vitro results confirmed the protective effect and aforementioned mechanisms of sesamol on sarcopenia. Collectively, sesamol could alleviate sarcopenia associated with aging and obesity via activating the AKT/mTOR/FoxO1 signal pathway. Our findings highlight the therapeutic potentials of sesamol for aging and obesity-related metabolic muscular complications., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Sarcopenia has become a prominent health problem among the elderly because of its adverse consequence, including physical disabilities and death. Fibro-adipogenic progenitors (FAPs) exhibit adipogenic and fibrogenic potencies and regulate skeletal muscle development, which plays important role in sarcopenia. Mairin, as an ingredient of Astragalus membranaceus, has the effect of anti-fibrosis. Therefore, we predicted that mairin targeted the fibrosis of FAPs and then affected sarcopenia. To verify our ideas, mairin (30 mg/kg/day or 60 mg/kg/day) was given to senescence accelerated mouse-prone 8 (SAMP8) mice by oral administration. Aging led to loss of weight, skeletal muscle mass, strength, and function, and an increase in muscle atrophy and fibrosis, while mairin administration inhibited physiological decline caused by aging. Similarly, mairin (20 μM or 40 μM) treatment enhanced FAP proliferation but blocked the differentiation into fibroblasts. Mechanically, mairin played an anti-fibrotic role via AMP-activated protein kinase-transforming growth factor beta-drosophila mothers against decapentaplegic protein (AMPK-TGF-β-SMAD) axis, as evidenced by increased phosphorylation of AMPKα and decreased TGF-β and phosphorylated-SMAD2/3. In addition, the potential target genes of mairin were explored by mRNA sequencing in our study. In conclusion, mairin may interfere with the AMPK/TGF-β/SMAD pathway to repress the fibrosis of FAPs and eventually ameliorate sarcopenia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The aging process is associated with the development of a wide range of degenerative disorders in mammals. These diseases are characterized by a progressive decline in function at multiple levels, including the molecular, cellular, tissue, and organismal. Furthermore, it is responsible for various healthcare costs in developing and developed countries. Sarcopenia is the deterioration in the quality and functionality of muscles, which is extremely concerning as it manages many functions in the human body. This article reviews the molecular crosstalk involved in sarcopenia and the specific roles of many mediator molecules in establishing cross-talk between muscles, bone, and fatty tissues, eventually leading to sarcopenia. Besides, the involvement of various etiological factors, such as neurology, endocrinology, lifestyle, etc., makes it exceedingly difficult for clinicians to develop a coherent hypothesis that may lead to the well-organized management system required to battle this debilitating disease. The several hallmarks contributing to the progression of the disease is a vital question that needs to be addressed to ensure an efficient treatment for sarcopenia patients. Also, the intricate molecular mechanism involved in developing this disease requires more studies. The direct relationship of cellular senescence with aging is one of the pivotal issues contributing to disease pathophysiology. Some patented treatment strategies have been discussed, including drugs undergoing clinical trials and emerging options like miRNA and protein-enclosed extracellular vesicles. A clear understanding of the secretome, including the signaling pathways involved between muscles, bone, and fatty tissues, is extremely beneficial for developing novel therapeutics for curing sarcopenia.

Sarcopenia is an aging-related skeletal disease characterized by decreased muscle mass, strength, and physical function, severely affecting the quality of life (QoL) of the elderly population. Sirtuin 1 (SIRT1), as a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in various aging-related signaling pathways and exert protective effect on many human diseases. SIRT1 functioned as an important role in the occurrence and progression of sarcopenia through regulating key pathways related to protein homeostasis, apoptosis, mitochondrial dysfunction, insulin resistance and autophagy in skeletal muscle, including SIRT1/Forkhead Box O (FoxO), AMP-activated protein kinase (AMPK)/SIRT1/nuclear factor κB (NF-κB), SIRT1/p53, AMPK/SIRT1/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), and SIRT1/live kinase B1 (LKB1)/AMPK pathways. However, the specific mechanisms of these processes have not been fully illuminated. Currently, several SIRT1-mediated interventions on sarcopenia have been preliminarily developed, such as SIRT1 activator polyphenolic compounds, exercising and calorie restriction. In this review, we summarized the predominant mechanisms of SIRT1 involved in sarcopenia and therapeutic modalities targeting the SIRT1 signaling pathways for the prevention and prognosis of sarcopenia., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Osteosarcopenia, which refers to the concomitant presence of osteoporosis and sarcopenia, is expected to increase in the rapidly progressive aging world, with serious clinical implications. However, the pathophysiology of osteosarcopenia has not been fully elucidated, and no optimal treatment specific to osteosarcopenia is available. The RANKL-RANK pathway is widely used as a therapeutic target for osteoporosis. Growing evidence supports the importance of the RANKL-RANK pathway, not only in bone, but also in muscle, and the therapeutic potential of targeting this pathway in muscle diseases has been noted. The muscles and bones closely communicate with each other through various secretory factors called myokines and osteokines. This review covers the roles of the RANKL-RANK pathway in the bone and muscle and their reciprocal interactions. Moreover, we will suggest future directions to move forward for the treatment of osteosarcopenia to prepare for an upcoming aging society.

Skeletal muscle, comprising a significant proportion (40 to 50 percent) of total body weight in humans, plays a critical role in maintaining normal physiological conditions. Muscle atrophy occurs when the rate of protein degradation exceeds protein synthesis. Sarcopenia refers to age-related muscle atrophy, while cachexia represents a more complex form of muscle wasting associated with various diseases such as cancer, heart failure, and AIDS. Recent research has highlighted the involvement of signaling pathways, including IGF1-Akt-mTOR, MuRF1-MAFbx, and FOXO, in regulating the delicate balance between muscle protein synthesis and breakdown. Myostatin, a member of the TGF-β superfamily, negatively regulates muscle growth and promotes muscle atrophy by activating Smad2 and Smad3. It also interacts with other signaling pathways in cachexia and sarcopenia. Inhibition of myostatin has emerged as a promising therapeutic approach for sarcopenia and cachexia. Additionally, other TGF-β family members, such as TGF-β1, activin A, and GDF11, have been implicated in the regulation of skeletal muscle mass. Furthermore, myostatin cooperates with these family members to impair muscle differentiation and contribute to muscle loss. This review provides an overview of the significance of myostatin and other TGF-β signaling pathway members in muscular dystrophy, sarcopenia, and cachexia. It also discusses potential novel therapeutic strategies targeting myostatin and TGF-β signaling for the treatment of muscle atrophy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstact: With advancing age, the incidence of sarcopenia increases, eventually leading to a cascade of adverse events. However, there is currently a lack of effective pharmacological treatment for sarcopenia. Sodium-glucose co-transporter 2 inhibitor (SGLT2i) empagliflozin demonstrates anti-fibrotic capabilities in various organs. This study aims to determine whether empagliflozin can improve skeletal muscle fibrosis induced by sarcopenia in naturally aging mice. A natural aging model was established by feeding male mice from 13 months of age to 19 months of age. A fibrosis model was created by stimulating skeletal muscle fibroblasts with TGF-β1. The Forelimb grip strength test assessed skeletal muscle function, and expression levels of COL1A1, COL3A1, and α-SMA were analyzed by western blot, qPCR, and immunohistochemistry. Additionally, levels of AMPKα/MMP9/TGFβ1/Smad signaling pathways were examined. In naturally aging mice, skeletal muscle function declines, expression of muscle fibrosis markers increases, AMPKα expression is downregulated, and MMP9/TGFβ1/Smad signaling pathways are upregulated. However, treatment with empagliflozin reverses this phenomenon. At the cellular level, empagliflozin exhibits similar anti-fibrotic effects, and these effects are attenuated by Compound C and siAMPKα. Empagliflozin exhibits anti-fibrotic effects, possibly associated with the AMPK/MMP9/TGFβ1/Smad signaling pathways., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Aging leads to a decrease in muscle function, mass, and strength in skeletal muscle of animals and humans. The transcriptome identified activation of the JAK/STAT pathway, a pathway that is associated with skeletal muscle atrophy, and endurance training has a significant effect on improving sarcopenia; however, the exact mechanism still requires further study. We investigated the effect of endurance training on sarcopenia. Six-month-old male SAMR1 mice were used as a young control group (group C), and the same month-old male SAMP8 mice were divided into an exercise group (group E) and a model group (group M). A 3-month running exercise intervention was performed on group E, and the other two groups were kept normally. Aging caused significant signs of sarcopenia in the SAMP8 mice, and endurance training effectively improved muscle function, muscle mass, and muscle strength in the SAMP8 mice. The expression of JAK2/STAT3 pathway factor was decreased in group E compared with group M, and the expression of SOCS3, the target gene of STAT3, and NR1D1, an atrophy-related factor, was significantly increased. Endurance training significantly improved the phenotypes associated with sarcopenia, and the JAK2/STAT3 pathway is a possible mechanism for the improvement of sarcopenia by endurance training, while NR1D1 may be its potential target. Keywords: Sarcopenia, Endurance training, Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3), Nuclear receptor subfamily 1, group D member 1 (Nr1d1).

Sarcopenia has a complex pathophysiology that encompasses metabolic dysregulation and muscle ultrastructural changes. Among the drivers of intracellular and ultrastructural changes of muscle fibers in sarcopenia, mitochondria and their quality control pathways play relevant roles. Mononucleated muscle stem cells/satellite cells (MSCs) have been attributed a critical role in muscle repair after an injury. The involvement of mitochondria in supporting MSC-directed muscle repair is unclear. There is evidence that a reduction in mitochondrial biogenesis blunts muscle repair, thus indicating that the delivery of functional mitochondria to injured muscles can be harnessed to limit muscle fibrosis and enhance restoration of muscle function. Injection of autologous respiration-competent mitochondria from uninjured sites to damaged tissue has been shown to reduce infarct size and enhance cell survival in preclinical models of ischemia-reperfusion. Furthermore, the incorporation of donor mitochondria into MSCs enhances lung and cardiac tissue repair. This strategy has also been tested for regeneration purposes in traumatic muscle injuries. Indeed, the systemic delivery of mitochondria promotes muscle regeneration and restores muscle mass and function while reducing fibrosis during recovery after an injury. In this review, we discuss the contribution of altered MSC function to sarcopenia and illustrate the prospect of harnessing mitochondrial delivery and restoration of MSCs as a therapeutic strategy against age-related sarcopenia.

Considering the expansion of human life-span over the past few decades; sarcopenia, a physiological consequence of aging process characterized with a diminution in mass and strength of skeletal muscle, has become more frequent. Thus, there is a growing need for expanding our knowledge on the molecular mechanisms of muscle atrophy in sarcopenia which are complex and involve many signaling pathways associated with protein degradation and synthesis. MicroRNAs (miRNAs) as evolutionary conserved small RNAs, could complementarily bind to their target mRNAs and post-transcriptionally inhibit their translation. Aberrant expression of miRNAs contributes to the development of sarcopenia by regulating the expression of critical genes involved in age-related skeletal muscle mass loss. Here we have a review on the signaling pathways along with the miRNAs controlling their components expression and subsequently we provide a brief overview on the effects of exercise on expression pattern of miRNAs in sarcopenia., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aims: Osteosarcopenia (OS), characterized by the coexistence of osteoporosis (OP) and sarcopenia (SP), is associated with high morbidity and mortality in the elderly. Nevertheless, its pathogenesis and treatment remain unclear. The aim of this study was to investigate the effect and mechanism of Zhuanggu Zhitong Capsule (ZGZT) in OS rats., Methods: All the related targets of OS, corresponding targets for bioactive ingredients of ZGZT, intersection targets of ZGZT against OS, and signaling pathways were predicted and analyzed by network pharmacology. Next, a rat OS model was established by ovariectomy (OVX) and injection of dexamethasone (DXM). Rats were then randomly divided into a Control group, a Sham operation group, an OS model group, an OS+ZGZT group, and an OS+E 2 group. The drug was given for 12 weeks. During treatment, body weight, forelimb grip and body composition were measured. In addition, bone mineral density (BMD) and micro CT were used to assess the left femur. After treatment, the left femur, left gastrocnemius, and left soleus, as well as uterus, liver, and kidney, were separated and analyzed using Histomorphology, Western blot, and quantitative real-time PCR (qRT-PCR)., Results: ZGZT could effectively improve the phenotypes of OS by increasing forelimb grip strength, percentage lean mass of the whole body (SMI) or appendicular lean (RSMI), BMD, levels of bone formation markers, improving the microstructure of femur, and decreasing apoptotic rate in femur and gastrocnemius in OS rats by up-regulating PI3K/Akt/Bcl2 signal pathway., Conclusions: ZGZT may be a new treatment option for the prevention and treatment of OS., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Sarcopenia, the age-related decline in muscle mass and function, derives from multiple etiological mechanisms. Accumulative research suggests that reactive oxygen species (ROS) generation plays a critical role in the development of this pathophysiological disorder. In this communication, we review the various signaling pathways that control muscle metabolic and functional integrity such as protein turnover, cell death and regeneration, inflammation, organismic damage, and metabolic functions. Although no single pathway can be identified as the most crucial factor that causes sarcopenia, age-associated dysregulation of redox signaling appears to underlie many deteriorations at physiological, subcellular, and molecular levels. Furthermore, discord of mitochondrial homeostasis with aging affects most observed problems and requires our attention. The search for the primary suspect of the fundamental mechanism for sarcopenia will likely take more intense research for the secret of this health hazard to the elderly to be unlocked.

The causes of the decline in skeletal muscle mass and function with age, known as sarcopenia, are poorly understood. Nutrition (calorie restriction) interventions impact many cellular processes and increase lifespan and preserve muscle mass and function with age. As we previously observed an increase in life span and muscle function in aging mice on a ketogenic diet (KD), we aimed to investigate the effect of a KD on the maintenance of skeletal muscle mass with age and the potential molecular mechanisms of this action. Twelve-month-old mice were assigned to an isocaloric control or KD until 16 or 26 months of age, at which time skeletal muscle was collected for evaluating mass, morphology, and biochemical properties. Skeletal muscle mass was significantly greater at 26 months in the gastrocnemius of mice on the KD. This result in KD mice was associated with a shift in fiber type from type IIb to IIa fibers and a range of molecular parameters including increased markers of NMJ remodeling, mitochondrial biogenesis, oxidative metabolism, and antioxidant capacity, while decreasing endoplasmic reticulum (ER) stress, protein synthesis, and proteasome activity. Overall, this study shows the effectiveness of a long-term KD in mitigating sarcopenia. The diet preferentially preserved oxidative muscle fibers and improved mitochondrial and antioxidant capacity. These adaptations may result in a healthier cellular environment, decreasing oxidative and ER stress resulting in less protein turnover. These shifts allow mice to better maintain muscle mass and function with age., (© 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Background/aims: Signaling and metabolic perturbations contribute to dysregulated skeletal muscle protein homeostasis and secondary sarcopenia in response to a number of cellular stressors including ethanol exposure. Using an innovative multiomics-based curating of unbiased data, we identified molecular and metabolic therapeutic targets and experimentally validated restoration of protein homeostasis in an ethanol-fed mouse model of liver disease., Methods: Studies were performed in ethanol-treated differentiated C2C12 myotubes and physiological relevance established in an ethanol-fed mouse model of alcohol-related liver disease (mALD) or pair-fed control C57BL/6 mice. Transcriptome and proteome from ethanol treated-myotubes and gastrocnemius muscle from mALD and pair-fed mice were analyzed to identify target pathways and molecules. Readouts including signaling responses and autophagy markers by immunoblots, mitochondrial oxidative function and free radical generation, and metabolic studies by gas chromatography-mass spectrometry and sarcopenic phenotype by imaging., Results: Multiomics analyses showed that ethanol impaired skeletal muscle mTORC1 signaling, mitochondrial oxidative pathways, including intermediary metabolite regulatory genes, interleukin-6, and amino acid degradation pathways are β-hydroxymethyl-butyrate targets. Ethanol decreased mTORC1 signaling, increased autophagy flux, impaired mitochondrial oxidative function with decreased tricarboxylic acid cycle intermediary metabolites, ATP synthesis, protein synthesis and myotube diameter that were reversed by HMB. Consistently, skeletal muscle from mALD had decreased mTORC1 signaling, reduced fractional and total muscle protein synthesis rates, increased autophagy markers, lower intermediary metabolite concentrations, and lower muscle mass and fiber diameter that were reversed by β-hydroxymethyl-butyrate treatment., Conclusion: An innovative multiomics approach followed by experimental validation showed that β-hydroxymethyl-butyrate restores muscle protein homeostasis in liver disease., Competing Interests: The authors have no conflicts to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Aging is associated with sarcopenia. The loss of strength results in decreased muscle mass and motor function. This process accelerates the progressive muscle deterioration observed in older adults, favoring the presence of debilitating pathologies. In addition, sarcopenia leads to a decrease in quality of life, significantly affecting self-sufficiency. Altogether, these results in an increase in economic resources from the National Health Systems devoted to mitigating this problem in the elderly, particularly in developed countries. Different etiological determinants are involved in the progression of the disease, including: neurological factors, endocrine alterations, as well as nutritional and lifestyle changes related to the adoption of more sedentary habits. Molecular and cellular mechanisms have not been clearly characterized, resulting in the absence of an effective treatment for sarcopenia. Nevertheless, physical activity seems to be the sole strategy to delay sarcopenia and its symptoms. The present review intends to bring together the data explaining how physical activity modulates at a molecular and cellular level all factors that predispose or favor the progression of this deteriorating pathology.

Sarcopenic obesity (SOB), which is closely related to being elderly as a feature of aging, is recently gaining attention because it is associated with many other age-related diseases that present as altered intercellular communication, dysregulated nutrient sensing, and mitochondrial dysfunction. Along with insulin resistance and inflammation as the core pathogenesis of SOB, autophagy has recently gained attention as a significant mechanism of muscle aging in SOB. Known as important cellular metabolic regulators, the AMP-activated protein kinase (AMPK) and the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) signaling pathways play an important role in autophagy, inflammation, and insulin resistance, as well as mutual communication between skeletal muscle, adipose tissue, and the liver. Furthermore, AMPK and PGC-1α signaling pathways are implicated in the gut microbiome-muscle axis. In this review, we describe the pathological link between SOB and its associated complications such as metabolic, cardiovascular, and liver disease, falls and fractures, osteoarthritis, pulmonary disease, and mental health via dysregulated autophagy controlled by AMPK and/or PGC-1α signaling pathways. Here, we propose potential treatments for SOB by modulating autophagy activity and gut dysbiosis based on plausible pathological links.

A unique property of skeletal muscle is its ability to adapt its mass to changes in activity. Inactivity, as in disuse or aging, causes atrophy, the loss of muscle mass and strength, leading to physical incapacity and poor quality of life. Here, through a combination of transcriptomics and transgenesis, we identify sestrins, a family of stress-inducible metabolic regulators, as protective factors against muscle wasting. Sestrin expression decreases during inactivity and its genetic deficiency exacerbates muscle wasting; conversely, sestrin overexpression suffices to prevent atrophy. This protection occurs through mTORC1 inhibition, which upregulates autophagy, and AKT activation, which in turn inhibits FoxO-regulated ubiquitin-proteasome-mediated proteolysis. This study reveals sestrin as a central integrator of anabolic and degradative pathways preventing muscle wasting. Since sestrin also protected muscles against aging-induced atrophy, our findings have implications for sarcopenia.

Musculoskeletal disorders are the leading cause of disability worldwide; two of the most prevalent of which are osteoporosis and sarcopenia. Each affect millions in the aging population across the world and the associated morbidity and mortality contributes to billions of dollars in annual healthcare cost. Thus, it is important to better understand the underlying pathologic mechanisms of the disease process. Regulatory chemokine, CXCL12, and its receptor, CXCR4, are recognized to be essential in the recruitment, localization, maintenance, development and differentiation of progenitor stem cells of the musculoskeletal system. CXCL12 signaling results in the development and functional ability of osteoblasts, osteoclasts, satellite cells and myoblasts critical to maintaining musculoskeletal homeostasis. Interestingly, one suggested pathologic mechanism of osteoporosis and sarcopenia is a decline in the regenerative capacity of musculoskeletal progenitor stem cells. Thus, because CXCL12 is critical to progenitor function, a disruption in the CXCL12 signaling axis might play a distinct role in these pathological processes. Therefore, in this article, we perform a review of CXCL12, its physiologic and pathologic function in bone and muscle, and potential targets for therapeutic development., (Published by Elsevier Ltd.)

There is a lack of pharmacological interventions available for sarcopenia, a progressive age-associated loss of muscle mass, leading to a decline in mobility and quality of life. We found mTORC1 (mammalian target of rapamycin complex 1), a well-established positive modulator of muscle mass, to be surprisingly hyperactivated in sarcopenic muscle. Furthermore, partial inhibition of the mTORC1 pathway counteracted sarcopenia, as determined by observing an increase in muscle mass and fiber type cross-sectional area in select muscle groups, again surprising because mTORC1 signaling has been shown to be required for skeletal muscle mass gains in some models of hypertrophy. Additionally, several genes related to senescence were downregulated and gene expression indicators of neuromuscular junction denervation were diminished using a low dose of a "rapalog" (a pharmacological agent related to rapamycin). Therefore, partial mTORC1 inhibition may delay the progression of sarcopenia by directly and indirectly modulating multiple age-associated pathways, implicating mTORC1 as a therapeutic target to treat sarcopenia., (Copyright © 2019 Joseph et al.)

Background: The concept of sarcopenic obesity refers to low muscle mass coupled with high adiposity in older adults. Sarcopenic obesity is a new medical challenge that imposes tremendous financial burdens on healthcare authorities worldwide. This study investigated the effects of resveratrol on high-fat diet-induced sarcopenic obesity in aged rats and palmitate acid-induced muscle atrophy in L6 myotubes and explored the underlying mechanisms., Results: In vivo , resveratrol prevented muscle loss and myofiber size decrease, improved grip strength and abolished excessive fat accumulation. In vitro , resveratrol inhibited the palmitate acid-mediated reductions in myosin heavy chain content and myotube diameter. Moreover, resveratrol ameliorated mitochondrial dysfunction and oxidative stress, leading to an improvement in protein metabolism and contributing to the prevention of muscle atrophy. Furthermore, the protective effects of resveratrol on mitochondrial function, oxidative stress and muscle atrophy were abolished by PKA siRNA, LKB1 siRNA and AMPK siRNA transfection in vitro ., Conclusions: Resveratrol prevented high-fat diet-induced muscle atrophy in aged rats by reversing mitochondrial dysfunction and oxidative stress, which was partially mediated by the PKA/LKB1/AMPK pathway. These findings indicate that resveratrol might have potential uses for the prevention and treatment of sarcopenic obesity.

With-no-lysine (K) (WNK) kinases, which are mutated in the inherited form of hypertension pseudohypoaldosteronism type II, are essential regulators of membrane ion transporters. Here, we report that WNK1 positively regulates skeletal muscle cell hypertrophy via mediating the function of the pro-longevity transcription factor forkhead box protein O4 (FOXO4) independent of the conventional WNK signaling pathway linking SPS/STE20-related proline-alanine-rich kinase (SPAK)/oxidative stress response kinase 1 (OSR1) to downstream effector ion transporters. Small interfering RNA (siRNA)-mediated silencing of WNK1, but not SPAK/OSR1 kinases, induced myotube atrophy and remarkable increases in the mRNA expression of the muscle atrophy ubiquitin ligases MAFbx and MuRF1 in C2C12 mouse skeletal muscle cells. WNK1 silencing also increased FOXO4 nuclear localization, and co-transfection of Foxo4-targeted siRNA completely reversed the myotube atrophy and upregulation of atrogene transcription induced by WNK1 silencing. We further illustrated that WNK1 protein abundance in skeletal muscle was increased by chronic voluntary wheel running exercise (hypertrophic stimulus) and markedly decreased by adenine-induced chronic kidney disease (atrophic stimulus) in mice. These findings suggest that WNK1 is involved in the physiological regulation of mammalian skeletal muscle hypertrophy and atrophy via interactions with FOXO4. The WNK1-FOXO4 axis may be a potential therapeutic target in human diseases causing sarcopenia.

The age-related loss of skeletal muscle (sarcopenia) is a major health concern as it is associated with physical disability, metabolic impairments, and increased mortality. The coexistence of sarcopenia with obesity, termed 'sarcopenic obesity', contributes to skeletal muscle insulin resistance and the development of type 2 diabetes, a disease prevalent with advancing age. Despite this knowledge, the mechanisms contributing to sarcopenic obesity remain poorly understood, preventing the development of targeted therapeutics. This article will discuss the clinical and physiological consequences of sarcopenic obesity and propose myostatin as a potential candidate contributing to this condition. A special emphasis will be placed on examining the role of myostatin signaling in impairing both skeletal muscle growth and insulin signaling. In addition, the role of myostatin in regulating muscle-to fat cross talk, further exacerbating metabolic dysfunction in the elderly, will be highlighted. Lastly, we discuss how this knowledge has implications for the design of myostatin-inhibitor clinical trials., Competing Interests: None declared by authors

Physical frailty in the elderly is driven by loss of muscle mass and function and hence preventing this is the key to reduction in age-related physical frailty. Our current understanding of the key areas in which ROS contribute to age-related deficits in muscle is through increased oxidative damage to cell constituents and/or through induction of defective redox signalling. Recent data have argued against a primary role for ROS as a regulator of longevity, but studies have persistently indicated that aspects of the aging phenotype and age-related disorders may be mediated by ROS. There is increasing interest in the effects of defective redox signalling in aging and some studies now indicate that this process may be important in reducing the integrity of the aging neuromuscular system. Understanding how redox-signalling pathways are altered by aging and the causes of the defective redox homeostasis seen in aging muscle provides opportunities to identify targeted interventions with the potential to slow or prevent age-related neuromuscular decline with a consequent improvement in quality of life for older people., (Copyright © 2016. Published by Elsevier Ltd.)

Background: Sarcopenia has been proposed as a potentially amenable factor impacting the clinical outcomes of hip-fractured elderly. The identification of specific biological targets is therefore crucial to developing pharmacological interventions against age-related muscle wasting. The present work reports promising preliminary data on the association between alterations of myocyte quality control (MQC) signaling and sarcopenia in old patients with hip fracture., Methods: Twenty-five elderly hip-fractured patients (20 women and 5 men; mean age 84.9±1.65years) were enrolled as part of the Sarcopenia in HIp FracTure (SHIFT) study. Intraoperative biopsies of the vastus lateralis muscle were obtained and assayed for the expression of a set of MQC signaling proteins. The presence of sarcopenia was established according to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria, with bioelectrical impedance analysis used for fat-free mass estimation., Results: Sarcopenia was identified in 10 patients (40%). Protein expression of the mitochondrial fusion factor mitofusin (Mfn) 2 and the autophagy mediator microtubule-associated protein 1 light chain 3B (LC3B) was significantly lower in patients with sarcopenia compared with non-sarcopenic controls. No differences between groups were observed for Mfn1, optic atrophy protein 1 (OPA1), fission protein 1 (Fis1), and the master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)., Conclusion: Data from this exploratory study show that a reduced expression of the mitochondrial fusion factor Mfn2 and the autophagy mediator LC3B is associated with sarcopenia in old hip-fractured patients. Future larger-scale studies are needed to corroborate these preliminary findings and determine whether MQC pathways may be targeted to improve muscle health and promote functional recovery in old patients with hip fracture., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Skeletal muscle mass plays a vital role in locomotion, whole-body metabolic health, and is a positive predictor of longevity. It is well established the mammalian target of rapamycin (mTOR) is a central regulator of skeletal muscle protein turnover. The pursuit to find novel nutrient compounds or functional food sources that possess the ability to activate mTOR and promote skeletal muscle protein accretion has been on going. Over the last decade, a key role has been proposed for the phospholipid phosphatidic acid (PA) in mTOR activation. Mechanical load-induced (i.e., resistance exercise) intramuscular PA can directly bind to and activate mTOR. In addition, PA provided exogenously in cell culture heightens mTOR activity, albeit indirectly. Thus, endogenously generated PA and exogenous provision of PA appear to act through distinct mechanisms that converge on mTOR and, potentially, may amplify muscle protein synthesis. In support of this notion, limited evidence from humans suggests that resistance exercise training combined with oral supplemental PA enhances strength gains and muscle hypertrophy. However, the precise mechanisms underpinning the augmented muscle remodelling response with supplemental PA remain elusive. In this review, we will critically examine available evidence from cell cultures and animal and human experimental models to provide an overview of the mechanisms through which endogenous and exogenous PA may act to promote muscle anabolism, and discuss the potential for PA as a therapeutic tool to maintain or restore skeletal muscle mass in the context of ageing and disease.

The world's elderly population is expanding rapidly, and we are now faced with the significant challenge of maintaining or improving physical activity, independence, and quality of life in the elderly. Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and often, frailty. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. Muscle loss has been linked with several proteolytic systems, including the ubuiquitin-proteasome, lysosome-autophagy, and tumor necrosis factor (TNF)-α/nuclear factor-kappaB (NF-κB) systems. Although many factors are considered to regulate age-dependent muscle loss, this gentle atrophy is not affected by factors known to enhance rapid atrophy (denervation, hindlimb suspension, etc.). In addition, defects in Akt-mammalian target of rapamycin (mTOR) and serum response factor (SRF)-dependent signaling have been found in sarcopenic muscle. Intriguingly, more recent studies indicated an apparent functional defect in autophagy- and myostatin-dependent signaling in sarcopenic muscle. In this review, we summarize the current understanding of the adaptation of many regulators in sarcopenia.

Changes in muscle mass may result from changes in protein turnover, reflecting the balance between protein synthesis and protein degradation, and changes in cell turnover, reflecting the balance between myonuclear accretion and myonuclear loss. Myonuclear accretion, i.e. increase in the number of myonuclei within the muscle fibers, takes place via proliferation and fusion of satellite cells, myogenic stem cells associated to skeletal muscle fibers and involved in muscle regeneration. In developing muscle, satellite cells undergo extensive proliferation and most of them fuse with myofibers, thus contributing to the increase in myonuclei during early postnatal stages. A similar process is induced in adult skeletal muscle by functional overload and exercise. In contrast, satellite cells and myonuclei may undergo apoptosis during muscle atrophy, although it is debated whether myonuclear loss occurs in atrophying muscle. An increase in myofiber size can also occur by changes in protein turnover without satellite cell activation, e.g. in late phases of postnatal development or in some models of muscle hypertrophy. The relative role of protein turnover and cell turnover in muscle adaptation and in the establishment of functional muscle hypertrophy remains to be established. The identification of the signaling pathways mediating satellite cell activation may provide therapeutic targets for combating muscle wasting in a variety of pathological conditions, including cancer cachexia, renal and cardiac failure, neuromuscular diseases, as well as aging sarcopenia., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Purpose of Review: Modifiers of TGFβ signaling have been investigated as treatment options for several types of muscle diseases. The purpose of this review is to focus on the most recent studies that have used this treatment strategy for pathological muscle disorders. We also review the recent insight into the mechanistic processes by which TGFβ signaling contributes to these pathologies by promoting fibrosis formation., Recent Findings: Recent research has shed light on the role of TGFβ signaling in the regulation of microRNAs associated with fibrosis formation. Inhibition of TGFβ signaling by Losartan treatment greatly improved the phenotype of myopathies associated with laminin-α2-deficient congenital muscular dystrophy. Caveolin 3 deficiency was also ameliorated by the use of several different types of TGFβ signaling inhibitors. Use of Losartan had dramatically beneficial effects on sarcopenic muscle by improving the regeneration after injury. Pharmacological manipulation to increase muscle mass is an emerging trend in obesity treatment research. New advances in the use of potent myostatin inhibitors have made this an attractive approach for future studies., Summary: An increasing number of skeletal myopathies are demonstrating favorable responses to alterations of the TGFβ signaling pathway. However, future research is needed to fully understand the downstream molecular signature associated with this pathway in order to develop more specific targeted therapies.

The neuromuscular junction (NMJ) is a specialized synapse between motor neurons and skeletal muscle with a complex signaling network that assures highly reliable neuromuscular transmission. Diseases of the NMJ cause skeletal muscle fatigue and include inherited and acquired disorders that affect presynaptic, intrasynaptic or postsynaptic components. Moreover, fragmentation of the NMJ contributes to sarcopenia, the loss of muscle mass during aging. Studies from recent years indicate that the formation and stabilization of NMJs differs between various muscles and that this difference affects their response under pathological conditions. This review summarizes the most important mechanisms involved in the development, maintenance and dysfunction of the NMJ and it discusses their significance in myasthenic disorders and aging and as targets for possible future treatment of NMJ dysfunction., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Physical exercise is the most effective intervention against sarcopenia of aging; however, the cellular and molecular mechanisms mediating training-induced adaptations are not yet completely understood. Furthermore, it is unclear whether exercise training initiated late in life affects myocyte anabolic signaling in a dose-dependent manner. Hence, we sought to investigate the effects of treadmill exercise and training frequency on anabolic pathways, including insulin signaling, in the skeletal muscle of old rats. Aged (14-16-month-old) male Wistar rats were trained on a treadmill for 3 (EX3) or 5 days/week (EX5) during 8 weeks and compared with age-matched sedentary controls (SED). Four-month-old rats were used as young controls (YC). Protein expression levels of insulin receptor (IR), insulin receptor substrate 1 (IRS-1), activated (phosphorylated) mammalian target of rapamycin (p-mTOR) and glucose transporter GLUT4 were determined in quadriceps muscle extracts via immunoblotting. Mitochondrial cytochrome c oxidase (COX) activity was assessed by histochemical staining, while electron microscopy was employed to quantify the sarcomere volume (V(src)). Body weight (BW) increased, whereas muscle weight (MW) and V(src) decreased with age. EX5, but not EX3 increased MW and V(src), without affecting BW. The expression of IR and GLUT4 was higher in SED rats relative to the YC group. Conversely, protein levels of IRS-1 and p-mTOR as well as COX activity were reduced in advanced age. Compared with SED rats, EX3 animals displayed reduced IR expression and increased IRS-1 levels and COX activity. The expression of GLUT 4 and p-mTOR was unaffected by EX3. EX5 up-regulated IRS-1 and p-mTOR expression and COX activity, while decreasing GLUT4 levels, with no effect on IR expression. In summary, substantial impairments in muscle anabolic pathways, including insulin signaling, were detected in aged sedentary rats. These changes were ameliorated by exercise training, concomitant with improvements in muscle trophism. Benefits were more evident in rats trained for 5 days/week, suggesting that physical exercise initiated late in life affects anabolic signaling in a dose-dependent manner., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Abnormal levels of reactive oxygen species (ROS) and inflammatory cytokines have been observed in the skeletal muscle during muscle wasting including sarcopenia. However, the mechanisms that signal ROS production and prolonged maintenance of ROS levels during muscle wasting are not fully understood. Here, we show that myostatin (Mstn) is a pro-oxidant and signals the generation of ROS in muscle cells. Myostatin, a transforming growth factor-β (TGF-β) family member, has been shown to play an important role in skeletal muscle wasting by increasing protein degradation. Our results here show that Mstn induces oxidative stress by producing ROS in skeletal muscle cells through tumor necrosis factor-α (TNF-α) signaling via NF-κB and NADPH oxidase. Aged Mstn null (Mstn(-/-) ) muscles, which display reduced sarcopenia, also show an increased basal antioxidant enzyme (AOE) levels and lower NF-κB levels indicating efficient scavenging of excess ROS. Additionally, our results indicate that both TNF-α and hydrogen peroxide (H(2) O(2) ) are potent inducers of Mstn and require NF-κB signaling for Mstn induction. These results demonstrate that Mstn and TNF-α are components of a feed forward loop in which Mstn triggers the generation of second messenger ROS, mediated by TNF-α and NADPH oxidase, and the elevated TNF-α in turn stimulates Mstn expression. Higher levels of Mstn in turn induce muscle wasting by activating proteasomal-mediated catabolism of intracellular proteins. Thus, we propose that inhibition of ROS induced by Mstn could lead to reduced muscle wasting during sarcopenia., (© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)