Abstract
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.
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Introduction
Skeletal muscle is a highly adaptable tissue that comprises approximately 40% of total body mass and is essential for maintaining limb posture and body movement. Skeletal muscle is also an endocrine organ that secretes myokines that have an effect on the whole-body organs [1,2,3]. Skeletal muscle atrophy is closely associated with some conditions such as sedentary, physical inactivity and cachexia [4, 5]. Skeletal muscle atrophy can seriously impact the quality of life of patients and increase the morbidity and mortality of many diseases. Muscle atrophy usually leads to the loss of muscle mass and function and is characterized by a reduction in muscle fiber size and mass, a conversion of muscle fiber type and an imbalance between protein synthesis and degradation in the muscle [6]. Under pathological conditions, skeletal muscle proteolysis is mainly mediated by the ubiquitin–proteasome system (UPS) and the autophagy-lysosome pathway (ALP). Muscle atrophy F-box (MAFbx) and muscle RING-finger protein-1 (MuRF1) are two muscle-specific E3 ubiquitin ligases in the UPS. During muscle atrophy, they are specifically expressed and target specific protein substrates for degradation in the UPS [7, 8]. The ALP is another important proteolysis system that removes misfolded or other harmful proteins, but its overactivation can lead to muscle atrophy [9]. Protein synthesis in skeletal muscle is mainly regulated by the IGF-1/PI3K/Akt/mTOR signaling axis, and activation of the mTOR pathway inhibits UPS and ALP in skeletal muscle [6, 10]. In addition, inflammation, oxidative stress and myofiber regeneration pathways also play a very important role in the process of muscle atrophy [11,12,13,14]. Overall, numerous molecules and complex signaling pathways have been involved in muscle atrophy; therefore, it is a major challenge for us to treat and prevent muscle atrophy.
Mitochondria are the site of ATP production and are involved in key metabolic pathways. Mitochondrial defects or dysregulation play a key role in the cytopathological mechanisms of aging, cancer, and neurodegenerative diseases [2, 15, 16]. During muscle atrophy, mitochondrial degradation influences the reduction of mitochondrial quality and quantity, which is controlled by mitochondrial autophagy as well as mitochondrial fusion and fission kinetics [17]. These mitochondrial quality-control systems are essential for the maintenance of skeletal muscle mass by recognizing and correcting mitochondrial dysfunction. Mitochondrial dysfunction triggers catabolic signaling pathways, which then will feed back to the nucleus to promote the expression of muscle atrophy genes [18]. As early as 1964, it was reported that mitochondrial dysfunction causes skeletal muscle atrophy [19]. Studies have indicated the effect of mitochondrial dysfunction on skeletal muscle atrophy. For example, in cisplatin-induced muscle atrophy, mitochondrial mass, membrane potential and reactive oxygen species (ROS) levels are abnormal. Therefore, reducing ROS production, rather than promoting ATP production, may be a therapeutic strategy to prevent cisplatin-induced muscle atrophy [20]. During muscle atrophy, denervation exacerbates mitochondrial dysregulation in muscle-specific knockout p53 tissues, suggesting that p53 promotes organ maintenance during muscle atrophy by regulating the mitochondrial quality-control process [21]. Furthermore, a clinical trial showed impaired mitochondrial function and significantly reduced level and activity of mitochondrial respiratory complex protein in pre-frail elderly (> 60 years of age) [22]. Therefore, it is an urgent task to provide an experimental basis for the treatment of muscle atrophy by targeting mitochondria.
Mitochondrial dysfunction has been recognized as an important sign of skeletal muscle atrophy, but its specific molecular mechanisms are unknown. Here, we review the role of normal mitochondria in skeletal muscle and the effects of mitochondrial dysfunction on skeletal muscle atrophy. Recent studies have also indicated that targeted modulation of mitochondrial function is an effective measure to treat and prevent skeletal muscle atrophy, which will provide an important target for develo** new drugs for muscle atrophy [2, 23, 24].
Literature search
This review focuses on a comprehensive review of the literature on mitochondria in skeletal muscle, as well as to review and analysis of the current evidences for mitochondrial dysregulation associated with skeletal muscle atrophy. The information related to the mitochondrial dysfunction were obtained from different databases and platforms, mainly PubMed, Scopus, Wiley Online Library, Springer Link, Web of Science, and Science Direct. The articles were from 1964 to 2023. After a thorough study and investigation of all the searched articles, 286 manuscripts were finally selected to complete this review based on the exclusion and inclusion criteria. More precisely, for this review, inclusion criteria included articles published in indexed and non-indexed journals, year of publication, and in vitro and in vivo investigations of mitochondria in skeletal muscle. Exclusion criteria included duplicate similar studies, poor statistical analyses, poorly written articles, poorly organized studies, and manuscripts of studies that did not meet the above inclusion criteria.
Molecular mechanism of skeletal muscle atrophy
More and more studies have shown that inflammation and oxidative stress play a crucial triggering role in the process of muscle atrophy [1, 24]. Inflammation and oxidative stress lead to increased proteolysis (ubiquitin–proteasome system, autophagic-lysosomal pathway, calpain and caspase-3), reduced protein synthesis, decreased regenerative capacity and increased fat infiltration and fibrosis (Fig. 1).
Molecular mechanism of skeletal muscle atrophy. Inflammation and oxidative stress lead to increased proteolysis, reduced protein synthesis, decreased regenerative capacity and increased fat infiltration and fibrosis
Inflammation and oxidative stress
Skeletal muscle atrophy is a state of uncontrolled inflammation and oxidative stress, which exacerbates proteolytic metabolism [25,26,27]. Inflammation induces skeletal muscle atrophy. During skeletal muscle injury, many key inflammatory mediators, especially inflammatory cytokines, are involved in repair process, including interferon-γ (IFN-γ), interleukin-6 (IL-6), transforming growth factor-β(TGF-β), and tumor necrosis factor-α (TNF-α) [1, 28]. Oxidative stress is a regulator of cellular signaling pathways, which influences energy metabolism, protein degradation and apoptosis in muscle through transcriptional and post-translational regulation of key proteins, leading to muscle mass loss and metabolic dysfunction [29, 30]. A transient elevation in oxidative stress levels may indicate an underlying health-promoting process, while uncontrolled accumulation of oxidative stress may have pathological implications [6, 31, 32]. Cyclooxygenase-2 (COX-2) is considered to be a positive regulator of pathophysiological processes, such as inflammation and oxidative stress, and silencing COX-2 blocks PDK1/TRAF4-induced activation of protein kinase B (AKT), which subsequently inhibits fibrogenesis after skeletal muscle atrophy [5, 33]. An anti-inflammatory drug, Triptolide, has been shown to prevent lipopolysaccharide-induced skeletal muscle atrophy by inhibiting the NF-κB/TNF-α pathway [34]. ROS, a by-product of mitochondrial metabolism, causes progressive damage to key cellular macromolecules (lipids, proteins and DNAs), and skeletal muscle is particularly susceptible due to its high metabolic rate [35]. During contractile activity, membrane-localized nicotinamide adenine dinucleotide phosphate oxidases (NAPDH) are a source of superoxide in skeletal muscle, which play an important role in redox signaling. In aging muscle, redox signaling dysregulation may lead to the loss of muscle fibers [36]. In addition, activation of toll-like receptor 2 induces oxidative stress and inflammation, while inhibition of toll-like receptor 2 attenuates skeletal muscle atrophy in a mouse model [37]. Salidroside and Tinospora cordifolia alleviate denervation-induced muscle atrophy by inhibiting oxidative stress and inflammation [12, 38, 39]. In the meantime, chronic inflammation can activate NAPDH oxidase and other inducible enzyme families that periodically promote the production of ROS and trigger further inflammation in skeletal muscle [40]. Therefore, inflammation and oxidative stress play an important regulatory role in the process of skeletal muscle atrophy, where inflammatory responses trigger oxidative stress responses and conversely, oxidative stress responses activate inflammatory responses.
Increased proteolysis
During skeletal muscle atrophy, the main proteolysis systems include UPS, ALP, calpain and caspase-3 [6, 41,42,43]. The UPS is responsible for the degradation of most misfolded or defective proteins in cells, which are modified through ubiquitination, that is, covalent binding to small proteins called ubiquitins. The ubiquitination process involves three enzymes, E1 ubiquitin activating enzyme, E2 ubiquitin coupling enzyme and E3 ubiquitin ligase, ultimately leading to the rapid degradation of muscle mass [44, 45]. MAFbx and MuRF1 were the first identified E3 ubiquitin ligases that play an important role in muscle atrophy, both of which are identified as the landmarks of muscle atrophy [46, 47]. They mediate the polyubiquitination of proteins and are eventually degraded by the 26S proteasome [48]. Under the condition of aging, injury and chronic disease, UPS is significantly activated, which destroys the homeostasis of protein and causes the accumulation of protein aggregates and the imbalance of redox [1, 5, 6, 49]. The ALP is an important proteolysis system in muscle atrophy [5, 7, 33, 50]. Autophagy can be divided into chaperone-mediated autophagy, micro-autophagy and macro-autophagy (hereinafter referred to as autophagy). The ALP is mainly involved in two processes, where autophagosomes deliver cytoplasmic components that are then degraded by lysosomal hydrolases [51]. FoxO3 is a key factor in the regulation of autophagy during skeletal muscle atrophy and controls the expression of several autophagy-related genes, the most important of which is BCL2/adenovirus E1B interacting protein 3 (BNIP3) [52]. In denervated skeletal muscle, lysosomal dysfunction may limit degradation capacity, leading to an inability to clear dysfunctional mitochondria and increased ROS signaling, thus accelerating muscle atrophy [53]. Both ALP and UPS are important pathways that regulate protein degradation in muscles and complement each other to play an important regulatory role in the control of muscle mass [54]. Calpain and caspase-3 act on the upstream of UPS to aid in the complete proteolysis of myofibrillar proteins [55]. Inhibition of calpain activity prevents caspase-3 activation, and inhibition of caspase-3 activity also prevents calpain activation. There is regulatory crosstalk between these proteases, which are required for fixation-induced muscle atrophy [56]. Increased protein oxidation triggers a progressive increase in the degradation of myofibrillar proteins using calpain and caspase-3, which may link oxidative stress to the accelerated proteolysis of myofibrillar protein during disuse atrophy [57]. After aspiration pneumonia, pro-inflammatory cytokines induce muscle proteolysis through activation of calpain and caspase-3, thereby causing skeletal muscle atrophy [58]. Superoxide-mediated oxidative stress leads to overall protein degradation and accelerates skeletal muscle atrophy through the activation of UPS and ALP, accompanied by the upregulation of calpain and caspase-3 [59]. Calpain and caspase-3 act synergistically to induce skeletal muscle proteolysis, with the potential to cause oxidative stress, thereby exacerbating skeletal muscle atrophy.
Reduced protein synthesis
Protein synthesis in skeletal muscle is a highly complex process that can be influenced by nutritional status, mechanical stimuli, repair procedures, hormones and growth factors [60]. Protein synthesis is controlled by the translation efficiency and capacity (the number of ribosomes) of mRNA into peptides [61]. Insulin-like growth factor-1 (IGF-1) is a key growth factor that regulates anabolic and catabolic pathways in skeletal muscle, and it promotes protein synthesis through the PI3K/Akt/ mTOR pathway [48]. MTORC1 activation leads to protein and lipid synthesis, and cellular growth [62]. In the skeletal muscle immobilized or disused state, mTORC1 and Akt signaling decreases, thus reducing muscle protein synthesis [63]. Hindlimb suspension-induced muscle atrophy results in increased protein synthesis and decreased protein degradation, and MAFbx and MuRF1 expression is also elevated in muscle [64]. Compared with wild-type mice, renalase-deficient mice could delay denervation-induced muscle atrophy via increased protein synthesis (Akt and p70S6K) [65]. In addition, both aerobic and resistance exercise can safely and effectively alleviate skeletal muscle atrophy by regulating myogenesis, protein synthesis and degradation, and apoptosis through the IGF-1/PI3K/Akt pathway in a mouse model of myocardial infarction [Obesity Obesity causes structural and functional changes in skeletal muscle, leading to the accumulation of intramuscular lipids, which is associated with impaired mitochondrial content and function in skeletal muscle [198]. Obesity also leads to renal mitochondrial dysfunction and energy imbalance, accelerating the progression of CKD and worsening CKD-dependent sarcopenia in mice [199]. Compared with sarcopenia or obesity alone, myopenic obesity is more likely to increase the risk of death, and patients with myopenic obesity have significantly lower expression of mitochondria-related proteins PGC-1α, MFN1, MFN2 and DRP1 than normal controls [200]. Furthermore, mitochondrial uncoupling may provide protection against myopenic obesity via enhancing skeletal muscle mitophagy and quality control to attenuate age-related decline in muscle mass and function [201]. Targeted regulation of mitochondrial dynamics, mitochondrial biogenesis and mitophagy seems to be an attractive treatment strategy for muscle atrophy caused by Obesity. ALS is a neurodegenerative disease accompanied by progressive loss of motor neurons, eventually leading to fatal paralysis [202, 203]. ALS was initially thought to be associated with oxidative stress, as it was first shown to be associated with the mutant SOD1, TDP-43 or other ALS-related mutant proteins that can all lead to mitochondrial imbalance in ALS and affect mitochondrial respiration as well as ATP production, calcium handling, mitochondrial dynamics and apoptotic signaling [204, 205]. ROS can lead to mitochondrial DNA mutations, membrane permeability and calcium homeostasis, as well as enhanced lipid oxidation and protein carbonylation, which will lead to various neurodegenerative diseases, including ALS [206]. Furthermore, a serum lipid analysis revealed a significant decrease in Cardiolipin content in the spinal cord of ALS rats, along with the loss of mitochondrial integrity [207]. Mitochondria are directly involved in the pathogenesis of ALS, but the causal relationship between mitochondrial dysfunction and ALS pathogenesis remains to be confirmed. SMA is caused by loss of function of survival motor neuron (SMN) protein, resulting in structural and functional alterations of the cytoskeleton in motor neurons and other cells [208]. SMN has been shown to affect mitochondrial and bioenergetic pathways and regulate the UPS function [209]. Impaired mitochondrial biogenesis can be observed both in the muscles o SMA patients and in the motor neurons of SMA mice, while the expression of the mitochondria-related genes TFAM, NRF1 and NRF2 is downregulated in the muscles of SMA patients [210]. In addition, SMA can increase the levels of oxidative stress and impair mitochondrial membrane potential in motor neurons, and fragmentation of mitochondrial networks in primary motor neurons of SMA mice is significantly increased [211]. The pathogenesis of SMA involves the proteolysis system and mitochondrial dysfunction, and their effects on SMN are required for further exploration. SBMA is an inherited neuromuscular disease characterized by motor neuron deficiency and skeletal muscle atrophy caused by polyglutamine expansion in the androgen receptor gene. Altered autophagy and mitochondrial defects underlie SBMA neuromuscular degeneration [212, 213]. In impaired motor neurons, an elevated synaptojanin 2 binding protein (SYNJ2BP) level (an outer mitochondrial membrane protein) alters the cellular distribution of mitochondria and increases mitochondrial-endoplasmic reticulum membrane contact sites, while lowering the SYNJ2BP level improves mitochondrial oxidative function [214]. Molecular links between epigenetic dysregulation of SBMA motor neurons and mitochondrial damage and metabolic dysfunction have been identified using gene expression analysis and ChIP sequencing [215]. These findings highlight the impact of mitochondrial dysfunction on SBMA and the search for potential biological targets is an urgent task for us. DMD is one of the most common and severe forms of muscle atrophy caused by mutations in the DMD gene encoding different isoforms of antimyotrophic proteins [216, 217]. DMD protein deficiency leads to intracellular Ca2+ dysregulation, mitochondrial dysfunction and increased ROS production [218]. Mitochondrial dysfunction is one of the first cellular changes in myofibers following DMD, as evidenced by mitochondrial dysfunction, abnormal mitochondrial morphology and mitophagy impairment (degradation of damaged mitochondria) [219]. In an mdx mouse model at 10–12 weeks of age, functional mitochondrial oxidative capacity was found to be disturbed, suggesting that mild oxidative stress reduces oxidative phosphorylation and thus declines ATP production [220]. In the future, we should pay attention to the impact of mitochondria-related pathways on DMD, which will lead to further understanding of the molecular mechanisms of DMD and potentially facilitate the discovery of DMD-targeted mitochondrial therapies.Amyotrophic lateral sclerosis (ALS)
Spinal muscular atrophy (SMA)
Spinal and bulbar muscular atrophy (SBMA)
Duchenne muscular dystrophy (DMD)
Therapeutic strategies targeting mitochondria for skeletal muscle atrophy
Mitochondria can provide sufficient energy for the life activities in cells. Mitochondrial dysfunction has been shown to play a very important role in the process of skeletal muscle atrophy. Targeted mitochondrial therapy has become an effective strategy, can directly regulate mitochondria, and improve treatment efficiency in skeletal muscle atrophy. At the same time, direct targeting of mitochondria may lead to fewer side effects on normal tissues. Targeted mitochondrial therapy has good biomedical prospects and is expected to provide new directions for clinical diagnosis and treatment. Strategies for improving mitochondrial function and delaying muscle atrophy mainly include mitochondria-targeted drug therapy (Mitochondria-targeted antioxidants, mitochondrial function activators, etc.), exercise and diet therapy, mitochondria-targeted gene therapy and other therapies (Fig. 4).
Therapeutic strategies targeting mitochondria for muscle atrophy. Strategies mainly include drug therapy, exercise and diet therapy, gene therapy and other therapies
Mitochondria-targeted drug therapy
Mitochondria-targeted antioxidants
So far, more and more mitochondrial targeting drugs have been reported. Meanwhile, the effective way to deliver drugs specifically to mitochondria is by covalent linking a lipophilic cation such as an alkyltriphenylphosphonium moiety to a pharmacophore of interest [221]. The combination of metformin and exercise improves mitochondrial bioenergetics and has beneficial effects against muscle loss and fat accumulation by regulating redox status [222]. Moreover, Mito-Met (metformin conjugated with TPP +) can enhance the targeting of metformin [221]. Resveratrol prevents high-fat diet-induced muscle atrophy in aged rats by reversing mitochondrial dysfunction and oxidative stress via the PKA/LKB1/AMPK pathway [223]. The mitochondria-targeted antioxidant XJB-5-131 increases the activity of electron transfer chain complexes in skeletal muscle mitochondria, reversing age-related alterations in mitochondrial function and improving contractility of skeletal muscles [224]. Mitoquinone Q improves mitochondrial homeostasis and metabolism, promotes β-oxidation in muscle tissue, and facilitates the glycolytic-oxidative transition in muscle metabolism and fiber composition [225]. Mitochondrial cardiolipid-targeted peptide, SS peptide, restores mitochondrial function, remodels mitochondria, repairs cellular structure, and promotes tissue regeneration during aging [226]. Szeto-Schiller 31, a mitochondria-targeted antioxidant peptide, prevents inactivity-induced decreased mitochondrial coupling and increased ROS emission to protect mitochondrial function and prevent muscle atrophy due to prolonged inactivity [23]. Szeto-Schiller 31 has shown promise in restoring mitochondrial bioenergetics viability in a phase I-II trial targeting heart failure and primary mitochondrial myopathy [227]. Astaxanthin, a red lutein carotenoid, promotes muscle health by reducing oxidative stress, myogenic apoptosis, and proteolysis pathways, and promoting mitochondrial regeneration and angiogenesis [228]. Trimetazidine, a partial inhibitor of lipid oxidation, prevents high-fat diet-induced muscle dysfunction by improving mitochondrial quality-control and mitochondrial function [229]. In addition, edaravone reverses oxidative stress-induced apoptosis and inhibits upregulation of mitochondrial ROS in induced pluripotent stem cell-derived spinal motor neurons from SMA patients. Therefore, it may be a therapeutic target for SMA [230]. Dysregulation of oxidative stress levels has been shown to be involved in the progression of skeletal muscle atrophy, so the specific use of antioxidants to target and modulate mitochondrial function would be a very effective intervention for muscle atrophy.
Mitochondrial function activators
5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) is an activator of AMPK that effectively improves mitochondrial and muscle function while maintaining the size of skeletal muscle in models of sarcopenia and cancer cachexia [2]. The age-related decreases in NRF2 signaling activity and mitochondrial dysfunction may be associated with the development of age-related diseases. Sulforaphane is a natural NRF2 activator. Cohorts of 2 month-old and 21- to 22 month-old mice were administered regular rodent diet or diet supplemented with Sulforaphane for 12 weeks. Sulforaphane restored Nrf2 activity, mitochondrial function, exercise capacity, glucose tolerance, and activation/differentiation of skeletal muscle satellite cells [231]. Furthermore, sulforaphane improves muscle function and pathology and protects dystrophic muscle from oxidative damage related to the NRF2 signaling pathway in mdx mice, with clinical implications for the treatment of patients with sarcopenia [232]. SRT2104 is a synthetic small molecule activator of SIRT1, and SRT2104 treatment improves systemic metabolic function, increases mitochondrial content, and preserves bone and muscle mass in an experimental model of atrophy [233]. CDN1163 is a novel small molecule allosteric activator of sarcoplasmic reticulum Ca2+ ATPase (SERCA) that reverses increased mitochondrial ROS generation and increased oxidative damage in muscle tissue in SOD1 mice, preventing oxidative stress-related muscle atrophy and weakness [234]. These activators can directly target molecules involved in mitochondrial dysfunction, providing potential targets for the development of new drugs to prevent and treat skeletal muscle atrophy.
Other drugs
During skeletal muscle aging, Lactobacillus paracasei PS23 protects mitochondrial function by reducing age-associated inflammation and ROS emission, thereby slowing age-related muscle loss [235]. In a mouse model of disuse muscle atrophy, Gomisin G (a lignan component of S. chinensis) enhances mitochondrial biogenesis and function through the SIRT1/PGC-1α signaling pathway to improve muscle strength [236]. Ginsenoside Rg3 protects against glucocorticoid-induced muscle atrophy by improving mitochondrial biogenesis and myotubular growth through the activation of PGC-1α [237]. Geranylgeraniol attenuates muscle atrophy in the flounder muscle of diabetic rats by altering mitochondrial mass [238]. Myricanol prevents against dexamethasone-induced muscle atrophy and myasthenia, reduces muscle protein degradation, enhances autophagy, and promotes mitochondrial biogenesis and function by activating SIRT1 in mice [239]. Dihydromyricetin reverses mitochondrial dysfunction via PGC-1α/TFAM and PGC-1α/MFN2 signaling pathways to attenuate dexamethasone-induced muscle atrophy [240]. Chrysanthemi Zawadskii var. Latilobum attenuates mitochondrial dysfunction in skeletal muscle of obese mice by modulating protein arginine methyltransferases, thereby alleviating obesity-induced skeletal muscle atrophy [241]. Paeoniflorin increases the activity of electron transport chain complexes and mitochondrial membrane potential, and improves skeletal muscle atrophy in CKD through AMPK/SIRT1/PGC-1α-mediated oxidative stress and mitochondrial dysfunction [242]. Urolithin A alleviates the symptoms of DMD by inducing mitophagy, increases skeletal muscle respiratory capacity, and improves muscle regeneration, which may have potential therapeutic applications in sarcopenia [243]. Olesoxime, a mitochondria-targeted drug for SMA, has been in phase III clinical trials. Olesoxime exerts its neuroprotective effects through modulation of mPTP to improve cell survival in multiple in vitro and in vivo models [244]. Oyster hydrolysate is a valuable natural material to inhibit skeletal muscle atrophy by regulating protein turnover and mitochondrial biogenesis [245]. Celecoxib alleviates denervation-induced muscle atrophy by reducing mitophagy and inhibiting oxidative stress [5]. Aspirin alleviates denervation-induced muscle atrophy and inhibits the shift from type I to type II muscle fiber and mitophagy via the SIRT1/PGC-1α axis and STAT3 signaling [246]. Levetiracetam is neuroprotective against SMA by ameliorating mitochondrial dysfunction in spinal motor neurons differentiated from SMA patient-derived induced pluripotent stem cells [247]. Mitochondria-targeted interventions using L-carnitine or teneligliptin can be used to treat CKD-induced muscle atrophy and decreased exercise tolerance [248]. Furthermore, ATG-125 is a phytochemical-rich herbal formulation that hinders sucrose-induced gastrocnemius muscle atrophy via rescuing Akt signaling and improving mitochondrial dysfunction in young adult mice [249]. Treatments with the pro-appetitive hormone ghrelin significantly increase mitochondrial respiratory capacity of C2C12 cells enhance muscle anabolism, and play an important role in preserving aging muscle [250]. In addition to antioxidants and activators, many other drugs such as Chinese herbs, anti-inflammatory drugs, and hormones can alleviate skeletal muscle atrophy by improving mitochondrial function. So, we need to focus on their long-term efficacy and safety.
Nanomedicine
In recent years, nanomedicine technology targeting mitochondria or cells has attracted increasing attention. Compared to conventional approaches, drug targeting with nanomaterials improves biocompatibility, safety, and specificity [251]. For example, nanomaterials have been used to enhance and mediate the functions of vascular cells (such as vascular endothelium and smooth muscle cells) and to prevent thrombosis and inflammation on stents in cardiovascular disease [251]. The polyphenols show protective antioxidant role in neurodegenerative disease at least partially due to their capacity to stimulate mitochondrial biogenesis and improve their function, which elevates mitochondrial efficiency resulting in diminished ROS production [252]. However, polyphenol compounds possess weak pharmacokinetics properties such as low bioavailability and solubility. The targeted polyphenol delivery by drug carriers created using nanotechnology that guarantees target specificity can overcome the drawbacks, and boost the bioavailability and stability of the therapeutic molecules in vivo [251]. Moreover, researches show that porous Se@SiO2 nanoparticles which would slowly release selenium could improve oxidative injury to promote muscle regeneration via modulating mitochondria [253]. CoQ’s lack of aqueous solubility and poor oral bioavailability contribute to suboptimal results observed with respect to the effect of CoQ supplements on statin-induced myopathy. Importantly, the nanodisk enhances CoQ bioavailability that represent a water-soluble vehicle capable of delivering CoQ to cultured myotubes [254]. However, there are still many challenges, such as the fabrication ad toxicity of nanomaterials. Such as, copper nanoclusters are increasingly being used in nanomedicine owing to their utility in cellular imaging and as catalysts. Additionally, exposure to CuNCs may be a risk factor for the skeletal muscle system [255]. More thorough studies of nanomedicine are still needed.
Exercise and diet
Exercise triggers an increase in key regulatory components of mitochondrial biogenesis (e.g., PGC-1, NRF1, and NRF2), and PGC-1 mediates a coordinated increase in GLUT4 and mitochondria [256]. Moreover, exercise attenuates UPS activity and increases the expression of mitophagy-related genes in skeletal muscle of patients with inflammatory myopathies [257]. It has been reported that exercise may inhibit muscle apoptosis, stimulate mitochondrial oxidative capacity and increase muscle blood flow by activating mTOR signaling and decreasing local TNF-α levels, thereby reversing sarcopenia in patients with cirrhosis [258]. In addition, aerobic exercise may help to inhibit the loss of mitochondrial content in skeletal muscle and forestall aging-induced complications of skeletal muscle, such as sarcopenia and insulin resistance [259]. Aerobic exercise can not only increase SIRT3 and PGC-1α expression levels in sedentary, overweight or obese adolescents, but it also enhances amino acid and carbohydrate intake in healthy older adults, which may prevent against muscle loss with age [260, 261]. Aerobic exercise has also been reported to improve mitochondrial function via Sestrin2 in an AMPKα2-dependent manner in sarcopenia mice [262]. Sedentary individuals present with decreased expression of skeletal muscle catabolism-related proteins (e.g., FoxO3a and MSTN), improved mitochondrial dynamics, and significant activation of signaling pathways associated with proliferation after aerobic exercise training, thereby favoring an increase in muscle fiber and overall muscle size, which may be associated with skeletal muscle hypertrophy [263]. Although endurance exercise training has long been thought to elevate aerobic capacity of skeletal muscle by enhancing mitochondrial quality-control and mitochondrial function, alternative exercise training that can induce similar improvements in mitochondria is gaining increasing attention as a viable intervention [264]. However frequent unaccustomed exercise can alter the structure and function of skeletal muscle fibers, which is called exercise-induced muscle damage. Exercise-induced muscle damage can lead to a temporary muscle damage and soreness that negatively affects muscle function [265]. In addition to exercise, attention to diet can also have a therapeutic effect on muscle atrophy. As nutritional supplements, polyphenols are plant-based compounds with antioxidant and anti-inflammatory properties, many of which are beneficial to human health and may delay skeletal muscle loss and functional impairment [266]. Long-term ketogenic diet slows aging-related muscle mass loss and increases mitochondrial content in aging skeletal muscle [267]. A ketogenic diet enhances mitochondrial biogenesis, oxidative metabolism, and antioxidant capacity in mice, and may protect skeletal muscle mass and function in aged mice [268]. Ketogenic diets combined with exercise alter mitochondrial function in human skeletal muscle while improving metabolic health [269]. In addition, branched-chain amino acids (BCAA: leucine, valine, isoleucine) have been shown to maintain body mass and cardiac function and prolong survival in rats with heart failure, possibly by increasing the expression of genes involved in mitochondrial biogenesis and skeletal muscle function [270]. Leucine is a branched-chain amino acid supplement that activates mTORC1, promotes protein synthesis and inhibits autophagy in muscle [271, 272]. Whereas drug therapy may carry risks such as side effects, exercise and diet seem to be relatively healthy treatments that will benefit the body from all aspects if adhered to over time.
Mitochondria-targeted gene therapy
Mitochondria belong to semi-automatic organelles, which have their own genome different from nuclear genome. Targeting genes involved in mitochondrial regulation and mitochondrial genes are of great significance for the treatment of skeletal muscle atrophy. PGC-1α overexpression preserves muscle size by inhibiting ALP and UPS and alleviating mitochondrial dysfunction, indicating that compounds that induce PGC-1α expression may benefit the treatment of muscle atrophy [273]. Overexpression of TFAM reduces skeletal muscle atrophy after hindlimb suspension in mice, which is correlated with the increased expression of antioxidants [274]. Parkin overexpression may prevent sepsis-induced skeletal muscle atrophy by improving mitochondrial mass and content [275]. Elevated SIRT1 expression leads to an increase in oxidative metabolism and mitochondrial biogenesis markers, thereby improving pathophysiological manifestations in a mouse model of DMD [276]. Histone deacetylase 4 (HDAC4) may inhibit mitophagy in denervated skeletal muscle and improve mitochondrial function through the direct regulation of myogenin, and therefore, the histone deacetylase 4-myogenin axis may function as a new target for the prevention and treatment of muscle atrophy [9]. Inhibition of the IL-6/JAK/STAT3 signaling pathway inhibits muscle atrophy and mitophagy, accompanied by a reduction in the expression of atrophy-related and autophagy-related genes, so the IL-6/JAK/STAT3 pathway can be used as a targeted strategy for skeletal muscle atrophy [14]. Furthermore, restoration of miR-181a levels in aged mice can prevent the accumulation of p62, DJ-1 and PARK2 and improve mitochondrial mass and muscle function [277]. lncRNA EDCH1 may improve mitochondrial function through SERCA2-mediated activation of the AMPK pathway to diminish muscle atrophy [278]. Early activation of lncRNA Pvt1 following muscle atrophy affects mitochondrial respiration and morphology and influences autophagy and apoptosis related to mitochondrial conformation and myofiber size, and thus targeting lncRNA Pvt1 may be a viable therapeutic target for muscle atrophy [279]. lncRNA Gm20743 may be involved in regulating mitochondrial function, oxidative stress, cell proliferation and myotube differentiation in skeletal muscle cells, and may be a potential therapeutic target for diabetes-induced sarcopenia [280]. Taken together, these genes and non-coding RNAs would be novel targets for targeting mitochondrial dysfunction in the treatment of muscle atrophy.
Other treatments
Extracellular vesicles are thought to be involved in many physiological and pathological processes, such as cancer progression, immune regulation, neurodegenerative diseases, and tissue regeneration [13]. Extracellular vesicles derived from skin precursor-derived Schwann cells can reduce mitochondrial vacuolar degeneration and autophagy in denervated muscles by inhibiting autophagy-associated proteins and alleviate muscle atrophy by suppressing oxidative stress and inflammatory responses [50]. Human umbilical cord-derived mesenchymal stromal cells ameliorate sarcopenia-associated skeletal muscle atrophy and dysfunction through AMPK-PGC-1α axis-mediated anti-apoptotic, anti-inflammatory, and mitochondrial biogenesis mechanisms [281]. Mesenchymal stem cell can mediate the transplantation of mitochondria into aging cells. This can restore the function of mitochondria in aging muscle cells and neurons, and then achieve the therapeutic purpose [282]. In addition, heat stress has been shown to trigger a stress response that leads to increased heat shock protein expression and improved mitochondrial function, while attenuating the reduction in human skeletal muscle mass and metabolic function due to immobilization [283]. Electrical stimulation can prevent against doxorubicin-induced muscle atrophy and mitochondrial loss in C2C12 myotubes [284]. Low-level laser irradiation prevents doxorubicin-induced skeletal muscle atrophy by preserving mitochondrial homeostasis and alleviating oxidative stress and apoptosis through the AMPK/SIRT1/PCG-1α pathway [285]. It has also been proposed that caloric restriction can delay sarcopenia by reducing oxygen radical production, decreasing oxidative stress damage, enhancing mitochondrial function, improving protein homeostasis, reducing iron overload, increasing autophagy and apoptosis, and reducing inflammation [286]. In conclusion, there are many ways to target mitochondria for the treatment of sarcopenia, and their mechanism is more worthy of our attention. In the future, the combined therapeutic modalities may be an alternative.
Prospects
Our understanding of the role of mitochondria in skeletal muscle atrophy has progressed considerably over the last few years. Mitochondria play a very important role in skeletal muscle growth and development, and mitochondrial dysfunction is an important cause of skeletal muscle atrophy. Therefore, the molecular mechanisms by which mitochondrial dysfunction induces skeletal muscle atrophy have attracted the interest of scientists. An understanding of these mechanisms could benefit the development of clinical treatment options for skeletal muscle atrophy, and future therapeutic strategies targeting mitochondria may be a key measure to prevent or treat different types of skeletal muscle atrophy. Currently the common therapeutic approaches are drug therapy, gene therapy, stem cell therapy and physiotherapy, and if additional combination therapeutic strategies can be developed or the feasibility of mitochondrial transplantation can be increased, the quality of life would be greatly improved in patients with muscle atrophy.
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This work was supported by the National Natural Science Foundation of China (Nos. 82072160, 32130060, 81901933), the Major Natural Science Research Projects in Universities of Jiangsu Province (No. 20KJA310012), the Natural Science Foundation of Jiangsu Province (Nos. BK20202013, BK20201209), the "QingLan Project" in Jiangsu Universities, the Priority Academic Program Development of Jiangsu Higher Education Institutions, and Nantong Science and Technology Program (Nos. JC22022037, JC2021085, MS22022010).
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XC, YJ and RL drafted the manuscript; XC, YJ, XZ, KW, XY, BL, ZG and YH contributed to the analysis of the results, YS, HL and HS reviewed and modified the manuscript. All authors agreed on the final version. All authors read and approved the final manuscript.
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Chen, X., Ji, Y., Liu, R. et al. Mitochondrial dysfunction: roles in skeletal muscle atrophy. J Transl Med 21, 503 (2023). https://doi.org/10.1186/s12967-023-04369-z
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DOI: https://doi.org/10.1186/s12967-023-04369-z