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Metabolism: Clinical and Experimental Aug 2023Muscles and bones are intricately connected tissues displaying marked co-variation during development, growth, aging, and in many diseases. While the diagnosis and... (Review)
Review
Muscles and bones are intricately connected tissues displaying marked co-variation during development, growth, aging, and in many diseases. While the diagnosis and treatment of osteoporosis are well established in clinical practice, sarcopenia has only been classified internationally as a disease in 2016. Both conditions are associated with an increased risk of adverse health outcomes such as fractures, dysmobility and mortality. Rather than focusing on one dimension of bone or muscle mass or weakness, the concept of musculoskeletal frailty captures the overall loss of physiological reserves in the locomotor system with age. The term osteosarcopenia in particular refers to the double jeopardy of osteoporosis and sarcopenia. Muscle-bone interactions at the biomechanical, cellular, paracrine, endocrine, neuronal or nutritional level may contribute to the pathophysiology of osteosarcopenia. The paradigm wherein muscle force controls bone strength is increasingly facing competition from a model centering on the exchange of myokines, osteokines and adipokines. The most promising results have been obtained in preclinical models where common drug targets have been identified to treat these conditions simultaneously. In this narrative review, we critically summarize the current understanding of the definitions, epidemiology, pathophysiology, and treatment of osteosarcopenia as part of an integrative approach to musculoskeletal frailty.
Topics: Humans; Sarcopenia; Frailty; Osteoporosis; Aging; Bone and Bones
PubMed: 37348597
DOI: 10.1016/j.metabol.2023.155638 -
Mitochondrial dysfunction and skeletal muscle atrophy: Causes, mechanisms, and treatment strategies.Mitochondrion Sep 2023Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in... (Review)
Review
Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in movement, posture and force production. More than just a component of the locomotor system, skeletal muscle functions as an endocrine organ capable of producing and secreting hundreds of bioactive molecules. Therefore, maintaining healthy skeletal muscles is crucial for supporting overall body health. Various pathological conditions, such as prolonged immobilization, cachexia, aging, drug-induced toxicity, and cardiovascular diseases (CVDs), can disrupt the balance between muscle protein synthesis and degradation, leading to skeletal muscle atrophy. Mitochondrial dysfunction is a major contributing mechanism to skeletal muscle atrophy, as it plays crucial roles in various biological processes, including energy production, metabolic flexibility, maintenance of redox homeostasis, and regulation of apoptosis. In this review, we critically examine recent knowledge regarding the causes of muscle atrophy (disuse, cachexia, aging, etc.) and its contribution to CVDs. Additionally, we highlight the mitochondrial signaling pathways involvement to skeletal muscle atrophy, such as the ubiquitin-proteasome system, autophagy and mitophagy, mitochondrial fission-fusion, and mitochondrial biogenesis. Furthermore, we discuss current strategies, including exercise, mitochondria-targeted antioxidants, in vivo transfection of PGC-1α, and the potential use of mitochondrial transplantation as a possible therapeutic approach.
Topics: Humans; Cachexia; Muscular Atrophy; Muscle, Skeletal; Mitochondria; Antioxidants
PubMed: 37451353
DOI: 10.1016/j.mito.2023.07.003 -
Journal of Translational Medicine Jul 2023Mitochondria play important roles in maintaining cellular homeostasis and skeletal muscle health, and damage to mitochondria can lead to a series of pathophysiological... (Review)
Review
Mitochondria play important roles in maintaining cellular homeostasis and skeletal muscle health, and damage to mitochondria can lead to a series of pathophysiological changes. Mitochondrial dysfunction can lead to skeletal muscle atrophy, and its molecular mechanism leading to skeletal muscle atrophy is complex. Understanding the pathogenesis of mitochondrial dysfunction is useful for the prevention and treatment of skeletal muscle atrophy, and finding drugs and methods to target and modulate mitochondrial function are urgent tasks in the prevention and treatment of skeletal muscle atrophy. In this review, we first discussed the roles of normal mitochondria in skeletal muscle. Importantly, we described the effect of mitochondrial dysfunction on skeletal muscle atrophy and the molecular mechanisms involved. Furthermore, the regulatory roles of different signaling pathways (AMPK-SIRT1-PGC-1α, IGF-1-PI3K-Akt-mTOR, FoxOs, JAK-STAT3, TGF-β-Smad2/3 and NF-κB pathways, etc.) and the roles of mitochondrial factors were investigated in mitochondrial dysfunction. Next, we analyzed the manifestations of mitochondrial dysfunction in muscle atrophy caused by different diseases. Finally, we summarized the preventive and therapeutic effects of targeted regulation of mitochondrial function on skeletal muscle atrophy, including drug therapy, exercise and diet, gene therapy, stem cell therapy and physical therapy. This review is of great significance for the holistic understanding of the important role of mitochondria in skeletal muscle, which is helpful for researchers to further understanding the molecular regulatory mechanism of skeletal muscle atrophy, and has an important inspiring role for the development of therapeutic strategies for muscle atrophy targeting mitochondria in the future.
Topics: Humans; Phosphatidylinositol 3-Kinases; Muscular Atrophy; Muscle, Skeletal; Mitochondria; Signal Transduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PubMed: 37495991
DOI: 10.1186/s12967-023-04369-z -
Biochemical Pharmacology Aug 2023Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle... (Review)
Review
Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle atrophy. In particular, oxidative stress is the key factor that triggers skeletal muscle atrophy. It is activated in the early stages of muscle atrophy and can be regulated by various factors. The mechanisms of oxidative stress in the development of muscle atrophy have not been completely elucidated. This review provides an overview of the sources of oxidative stress in skeletal muscle and the correlation of oxidative stress with inflammation, mitochondrial dysfunction, autophagy, protein synthesis, proteolysis, and muscle regeneration in muscle atrophy. Additionally, the role of oxidative stress in skeletal muscle atrophy caused by several pathological conditions, including denervation, unloading, chronic inflammatory diseases (diabetes mellitus, chronic kidney disease, chronic heart failure, and chronic obstructive pulmonary disease), sarcopenia, hereditary neuromuscular diseases (spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy), and cancer cachexia, have been discussed. Finally, this review proposes the alleviation oxidative stress using antioxidants, Chinese herbal extracts, stem cell and extracellular vesicles as a promising therapeutic strategy for muscle atrophy. This review will aid in the development of novel therapeutic strategies and drugs for muscle atrophy.
Topics: Humans; Muscular Atrophy; Oxidative Stress; Muscle, Skeletal; Sarcopenia; Antioxidants; Chronic Disease
PubMed: 37331636
DOI: 10.1016/j.bcp.2023.115664 -
Archives of Disease in Childhood Jul 2023Spinal muscular atrophy (SMA) is a severe neurodegenerative condition due to recessive mutations in the gene resulting in insufficiency of survival motor neuron (SMN)... (Review)
Review
Spinal muscular atrophy (SMA) is a severe neurodegenerative condition due to recessive mutations in the gene resulting in insufficiency of survival motor neuron (SMN) protein. Lack of SMN protein results in irreversible degeneration of lower motor neurons and consequential muscle atrophy and weakness. , a homologue, produces low levels of functional SMN protein with the potential to partially compensate loss. Several compounds have been shown to successfully restore SMN protein production in motor neurons, either by enhancing gene function or by direct replacement of the gene. Clinical trials of these compounds have demonstrated the potential to substantially alter the natural history of SMA and have led to their implementation into clinical practice. To date, 3 novel drugs, nusinersen, onasemnogene aberparvovec and risdiplam, have received marketing authorisation for SMA treatment by several authorities including Food and Drug Administration and European Medicines Agency. While implementing these drugs into daily clinical practice, clinicians face a number of new challenges, including identifying the most advantageous treatment for any individual, optimisation of outcomes and management of a modified SMA phenotype. Considering that treatment initiation at the pre-symptomatic or paucisymptomatic stage appears to be associated with better outcomes, health services need to support early diagnosis for this now treatable condition. This review aims to give an overview of the current therapeutic landscape of SMA, to provide an understanding of current practice of SMA management and to help increase awareness of the imminent need for urgent early diagnosis at the pre-symptomatic stage.
Topics: United States; Humans; Muscular Atrophy, Spinal; Mutation; Phenotype
PubMed: 36316089
DOI: 10.1136/archdischild-2021-323605 -
Cancer Cell May 2024With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune...
With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.
Topics: Cachexia; Pancreatic Neoplasms; Cytokine TWEAK; Animals; Humans; Macrophages; Mice; NF-kappa B; Cell Line, Tumor; Tumor Microenvironment; Muscular Atrophy; Chemokine CCL5; Signal Transduction; TNF Receptor-Associated Factor 6; Tumor Necrosis Factors; Receptors, CCR2; Chemokine CCL2; Mice, Inbred C57BL
PubMed: 38608702
DOI: 10.1016/j.ccell.2024.03.009 -
Journal of Cachexia, Sarcopenia and... Aug 2023Although the adiponectin signalling exerts exercise-mimicking effects, whether this pathway contributes to the anti-ageing benefits of physical exercise has not been...
BACKGROUND
Although the adiponectin signalling exerts exercise-mimicking effects, whether this pathway contributes to the anti-ageing benefits of physical exercise has not been established yet.
METHODS
Swim exercise training and wheel running were used to measure lifespan in the nematode Caenorhabditis elegans and skeletal muscle quality in mice, respectively. Muscle weight, muscle fibre cross-sectional area (CSA) and myonuclei number were used to evaluate muscle mass. RNA sequencing (RNA-Seq) analysis of skeletal muscle in exercised mice was used to study the underlying mechanisms. Western blot and immunofluorescence were performed to explore autophagy- and senescence-related markers.
RESULTS
The C. elegans adiponectin receptor PAQR-1/AdipoR1, but not PAQR-2/AdipoR2, was activated (3.55-fold and 3.48-fold increases in p-AMPK on Days 1 and 6, respectively, P < 0.001), which was involved in lifespan extension in exercised worms. Exercise training increased skeletal muscle mass index (1.29-fold, P < 0.01), muscle weight (1.75-fold, P < 0.001), myonuclei number (1.33-fold, P < 0.05), muscle fibre CSA (1.39-fold, P < 0.05) and capillary abundance (2.19-fold, P < 0.001 for capillary density; 1.58-fold, P < 0.01 for capillary number) in aged mice. Physical exercise reduced protein (2.94-fold, P < 0.001) and mRNA levels (1.70-fold, P < 0.001) of p16 , a marker for cellular senescence, in skeletal muscle of aged mice. These beneficial effects of exercise on skeletal muscle of mice were dependent on AdipoR1. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis for differentially expressed genes in skeletal muscle between exercised mice with and without AdipoR1 knockdown by RNA-Seq analysis revealed that several KEGG pathways, such as 'AMPK signalling pathway' (P < 0.001), 'FOXO signalling pathway' (P < 0.001) and 'autophagy' (P < 0.001) were overrepresented. Knockdown of FoxO3a inhibited exercise-mediated beneficial effects on skeletal muscle quality of mice by inhibiting autophagy/mitophagy (3.81-fold reduction in LC3-II protein, P < 0.001; 1.53-fold reduction in BNIP3 protein, P < 0.05). Knockdown of daf-16, the FoxO homologue in C. elegans, reduced autophagy (2.77-fold and 2.06-fold reduction in GFP::LGG-1 puncta in seam cells and the intestine, respectively, P < 0.05) and blocked lifespan extension by exercise in worms.
CONCLUSIONS
Our findings provide insights into how the AdipoR1 pathway has an impact on the anti-ageing benefits of exercise and implicate that activation of the AdipoR1 signalling may represent a potential therapeutic strategy for reducing age-related loss of skeletal muscle.
Topics: Mice; Animals; Receptors, Adiponectin; AMP-Activated Protein Kinases; Caenorhabditis elegans; Motor Activity; Muscle, Skeletal; Aging; Muscular Atrophy
PubMed: 37222007
DOI: 10.1002/jcsm.13257 -
Nature Communications Aug 2023To maintain and restore skeletal muscle mass and function is essential for healthy aging. We have found that myonectin acts as a cardioprotective myokine. Here, we...
To maintain and restore skeletal muscle mass and function is essential for healthy aging. We have found that myonectin acts as a cardioprotective myokine. Here, we investigate the effect of myonectin on skeletal muscle atrophy in various male mouse models of muscle dysfunction. Disruption of myonectin exacerbates skeletal muscle atrophy in age-associated, sciatic denervation-induced or dexamethasone (DEX)-induced muscle atrophy models. Myonectin deficiency also contributes to exacerbated mitochondrial dysfunction and reduces expression of mitochondrial biogenesis-associated genes including PGC1α in denervated muscle. Myonectin supplementation attenuates denervation-induced muscle atrophy via activation of AMPK. Myonectin also reverses DEX-induced atrophy of cultured myotubes through the AMPK/PGC1α signaling. Furthermore, myonectin treatment suppresses muscle atrophy in senescence-accelerated mouse prone (SAMP) 8 mouse model of accelerated aging or mdx mouse model of Duchenne muscular dystrophy. These data indicate that myonectin can ameliorate skeletal muscle dysfunction through AMPK/PGC1α-dependent mechanisms, suggesting that myonectin could represent a therapeutic target of muscle atrophy.
Topics: Animals; Male; Mice; AMP-Activated Protein Kinases; Mice, Inbred mdx; Muscle, Skeletal; Muscular Atrophy; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
PubMed: 37542026
DOI: 10.1038/s41467-023-40435-2 -
Journal of Cachexia, Sarcopenia and... Oct 2023DJ-1 is a causative gene for Parkinson's disease. DJ-1-deficient mice develop gait-associated progressive behavioural abnormalities and hypoactive forearm grip strength....
BACKGROUND
DJ-1 is a causative gene for Parkinson's disease. DJ-1-deficient mice develop gait-associated progressive behavioural abnormalities and hypoactive forearm grip strength. However, underlying activity mechanisms are not fully explored.
METHODS
Western blotting and quantitative real-time polymerase chain reaction approaches were adopted to analyse DJ-1 expression in skeletal muscle from aged humans or mice and compared with young subjects. Skeletal muscle-specific-DJ-1 knockout (MDKO) mice were generated, followed by an assessment of the physical activity phenotypes (grip strength, maximal load capacity, and hanging, rotarod, and exercise capacity tests) of the MDKO and control mice on the chow diet. Muscular atrophy phenotypes (cross-sectional area and fibre types) were determined by imaging and quantitative real-time polymerase chain reaction. Mitochondrial function and skeletal muscle morphology were evaluated by oxygen consumption rate and electron microscopy, respectively. Tail suspension was applied to address disuse atrophy. RNA-seq analysis was performed to indicate molecular changes in muscles with DJ-1 ablation. Dual-luciferase reporter assays were employed to identify the promoter region of Trim63 and Fbxo32 genes, which were indirectly regulated by DJ-1 via the FoxO1 pathway. Cytoplasmic and nuclear fractions of DJ-1-deleted muscle cells were analysed by western blotting. Compound 23 was administered into the gastrocnemius muscle to mimic the of DJ-1 deletion effects.
RESULTS
DJ-1 expression decreased in atrophied muscles of aged human (young men, n = 2; old with aged men, n = 2; young women, n = 2; old with aged women, n = 2) and immobilization mice (n = 6, P < 0.01). MDKO mice exhibited no body weight difference compared with control mice on the chow diet (Flox, n = 8; MDKO, n = 9). DJ-1-deficient muscles were slightly dystrophic (Flox, n = 7; MDKO, n = 8; P < 0.05), with impaired physical activities and oxidative capacity (n = 8, P < 0.01). In disuse-atrophic conditions, MDKO mice showed smaller cross-sectional area (n = 5, P < 0.01) and more central nuclei than control mice (Flox, n = 7; MDKO, n = 6; P < 0.05), without alteration in muscle fibre types (Flox, n = 6; MDKO, n = 7). Biochemical analysis indicated that reduced mitochondrial function and upregulated of atrogenes induced these changes. Furthermore, RNA-seq analysis revealed enhanced activity of the FoxO1 signalling pathway in DJ-1-ablated muscles, which was responsible for the induction of atrogenes. Finally, compound 23 (an inhibitor of DJ-1) could mimic the effects of DJ-1 ablation in vivo.
CONCLUSIONS
Our results illuminate the crucial of skeletal muscle DJ-1 in the regulation of catabolic signals from mechanical stimulation, providing a therapeutic target for muscle wasting diseases.
Topics: Male; Humans; Animals; Female; Mice; Aged; Muscle, Skeletal; Muscular Atrophy; Muscle Fibers, Skeletal; Muscular Disorders, Atrophic; Mitochondria
PubMed: 37469245
DOI: 10.1002/jcsm.13290