scholarly journals Mitochondrial Dysfunction Is a Common Denominator Linking Skeletal Muscle Wasting Due to Disease, Aging, and Prolonged Inactivity

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 588
Author(s):  
Hayden W. Hyatt ◽  
Scott K. Powers
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dysfunction ◽  
Chronic Diseases ◽  
Muscle Mass ◽  
Cancer Chemotherapy ◽  
Muscle Wasting ◽  
The Body ◽  
Common Denominator ◽  
Skeletal Muscle Wasting ◽  
Vital Functions

Skeletal muscle is the most abundant tissue in the body and is required for numerous vital functions, including breathing and locomotion. Notably, deterioration of skeletal muscle mass is also highly correlated to mortality in patients suffering from chronic diseases (e.g., cancer). Numerous conditions can promote skeletal muscle wasting, including several chronic diseases, cancer chemotherapy, aging, and prolonged inactivity. Although the mechanisms responsible for this loss of muscle mass is multifactorial, mitochondrial dysfunction is predicted to be a major contributor to muscle wasting in various conditions. This systematic review will highlight the biochemical pathways that have been shown to link mitochondrial dysfunction to skeletal muscle wasting. Importantly, we will discuss the experimental evidence that connects mitochondrial dysfunction to muscle wasting in specific diseases (i.e., cancer and sepsis), aging, cancer chemotherapy, and prolonged muscle inactivity (e.g., limb immobilization). Finally, in hopes of stimulating future research, we conclude with a discussion of important future directions for research in the field of muscle wasting.

scholarly journals Glycogen Synthase Kinase-3β Inhibitor Lithium Chloride Protects Against Inflammation-Mediated Skeletal Muscle Wasting

2021 ◽  
Author(s):  
Ji-Hyung Lee ◽  
Seon-Wook Kim ◽  
Jun-Hyeong Kim ◽  
Hyung-Jun Kim ◽  
JungIn Um ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Lithium Chloride ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Glycogen Synthase ◽  
Conditioned Media ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β ◽  
Skeletal Muscle Wasting

Abstract Inflammation-mediated skeletal muscle wasting is induced by inflammatory cytokines. It occurs in critically ill patients with sepsis (termed intensive care unit acquired weakness) and patients with advanced metastasis (termed cancer cachexia). Both conditions severely impact on patient morbidity and mortality. Lithium chloride has been investigated as a drug repurposing candidate for numerous diseases. In this study, we assessed whether lithium chloride affects inflammation-mediated muscle wasting, using in vitro and in vivo models of cancer cachexia and sepsis. Lithium chloride prevented wasting in myotubes cultured with cancer cell conditioned media, maintained expression of the muscle fiber contractile protein, myosin heavy chain 2 and blocked upregulation of the E3 ubiquitin ligase, Atrogin-1. Glycogen synthase kinase-3β inhibition was indicated as the target mechanism, due to the following observations: 1) β-catenin was upregulated in the myotubes and 2) inhibition of IMPA1, the secondary biological target of lithium chloride, did not inhibit the effects of cancer conditioned media. Lithium chloride inhibited upregulation of the inflammation-associated cytokines Il-1β, Il-6 and inos in macrophages treated with lipopolysaccharide. Lithium chloride treatment in an animal model of sepsis improved body weight, increased muscle mass, preserved the survival of larger fibers and decreased expression of the wasting effector genes, Atrogin-1 and Murf-1. In a model of cancer cachexia, lithium chloride increased muscle mass, enhanced muscle strength and increased fiber cross sectional area, with no significant effect on tumorigenesis. These results indicate that lithium chloride could be repurposed as a drug to treat patients with inflammation-mediated skeletal muscle wasting.

scholarly journals SUN-140 TMEPAI Inhibits SMAD 2/3 Mediated Muscle Wasting

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Swati Kharoud ◽  
Kelly Louise Walton ◽  
Adam Hagg ◽  
Georgia Goodchild ◽  
Justin Chen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Gene Delivery ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Activin A ◽  
Viral Gene ◽  
Soluble Receptors ◽  
Skeletal Muscle Wasting ◽  
Viral Gene Delivery

Abstract Inhibition of myostatin and activin activity using ligand traps, such as soluble receptors, follistatin and propeptides, can markedly increase skeletal muscle mass in healthy mice and ameliorate wasting in models of cancer cachexia and muscular dystrophy. Though effective, clinical translation of these approaches has been hindered by off-target effects. Toward the goal of developing tissue-specific myostatin/activin interventions, we explored the ability of transmembrane prostate androgen-induced (TMEPAI) to promote growth of skeletal muscle. TMEPAI, a transcriptional target of activin in muscle, is a known inhibitor of TGF-β1-mediated SMAD 2/3 signalling. In this study we show that TMEPAI also blocks activin A, activin B, myostatin and GDF-11 in vitro activity. Adeno-associated viral (AAV) gene delivery of TMEPAI into healthy mice increased local muscle mass by as much as 30%. Increased muscle mass was attributed to hypertrophy of fibres in TMEPAI-expressing muscles, and was coincident with an upregulation in markers of protein synthesis (pAkt, pMTOR, p70S6K). The ability of TMEPAI to block activation of the canonical activin/myostatin-SMAD 2/3 axis, was demonstrated by co-injecting AAV6:activin A and AAV6:TMEPAI into healthy mice. In this setting, TMEPAI blocked activin-induced phosphorylation of SMAD3 and associated skeletal muscle wasting. Finally, delivery of AAV6:TMEPAI into tibialis anterior muscles of mice bearing C26 tumours prevented muscle atrophy normally associated with this model. The results support that viral gene delivery of TMEPAI can effectively increase muscle mass via inactivation of the activin/myostatin-SMAD 2/3 pathway.

scholarly journals Angiotensin II suppresses autophagy and disrupts ultrastructural morphology and function of mitochondria in mouse skeletal muscle

2019 ◽  
Vol 126 (6) ◽  
pp. 1550-1562 ◽  
Author(s):  
Kleiton Augusto Santos Silva ◽  
Thaysa Ghiarone ◽  
Kathy Schreiber ◽  
DeAna Grant ◽  
Tommi White ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Angiotensin Ii ◽  
Protein Expression ◽  
Chronic Diseases ◽  
Muscle Wasting ◽  
Beclin 1 ◽  
Ang Ii ◽  
Autophagosome Formation ◽  
Skeletal Muscle Wasting ◽  
And Function

Angiotensin II (ANG II)-induced skeletal muscle wasting is characterized by activation of the ubiquitin-proteasome system. However, the potential involvement of proteolytic system macroautophagy/autophagy in this wasting process remains elusive. Autophagy is precisely regulated to maintain cell survival and homeostasis; thus its dysregulation (i.e., overactivation or persistent suppression) could lead to detrimental outcomes in skeletal muscle. Here we show that infusion of ANG II for 7 days in male FVB mice suppressed autophagy in skeletal muscle. ANG II blunted microtubule-associated protein 1 light chain 3B (LC3B)-I-to-LC3B-II conversion (an autophagosome marker), increased p62/SQSTM1 (an autophagy cargo receptor) protein expression, and decreased the number of autophagic vacuoles. ANG II inhibited UNC-51-like kinase 1 via inhibition of 5′-AMP-activated kinase and activation of mechanistic target of rapamycin complex 1, leading to reduced phosphorylation of beclin-1Ser14 and Autophagy-related protein 14Ser29, suggesting that ANG II impairs autophagosome formation in skeletal muscle. In line with ANG II-mediated suppression of autophagy, ANG II promoted accumulation of abnormal/damaged mitochondria, characterized by swelling and disorganized cristae and matrix dissolution, with associated increase in PTEN-induced kinase 1 protein expression. ANG II also reduced mitochondrial respiration, indicative of mitochondrial dysfunction. Together, these results demonstrate that ANG II reduces autophagic activity and disrupts mitochondrial ultrastructure and function, likely contributing to skeletal muscle wasting. Therefore, strategies that activate autophagy in skeletal muscle have the potential to prevent or blunt ANG II-induced skeletal muscle wasting in chronic diseases. NEW & NOTEWORTHY Our study identified a novel mechanism whereby angiotensin II (ANG II) impairs mitochondrial energy metabolism in skeletal muscle. ANG II suppressed autophagosome formation by inhibiting the UNC-51-like kinase 1(ULK1)-beclin-1 axis, resulting in accumulation of abnormal/damaged and dysfunctional mitochondria and reduced mitochondrial respiratory capacity. Therapeutic strategies that activate the ULK1-beclin-1 axis have the potential to delay or reverse skeletal muscle wasting in chronic diseases characterized by increased systemic ANG II levels.

scholarly journals Lithium Chloride Protects against Sepsis-Induced Skeletal Muscle Atrophy and Cancer Cachexia

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1017
Author(s):  
Ji-Hyung Lee ◽  
Seon-Wook Kim ◽  
Jun-Hyeong Kim ◽  
Hyun-Jun Kim ◽  
JungIn Um ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Lithium Chloride ◽  
Muscle Atrophy ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Therapeutic Effects ◽  
In Vivo Models ◽  
Skeletal Muscle Wasting ◽  
Chloride Treatment

Inflammation-mediated skeletal muscle wasting occurs in patients with sepsis and cancer cachexia. Both conditions severely affect patient morbidity and mortality. Lithium chloride has previously been shown to enhance myogenesis and prevent certain forms of muscular dystrophy. However, to our knowledge, the effect of lithium chloride treatment on sepsis-induced muscle atrophy and cancer cachexia has not yet been investigated. In this study, we aimed to examine the effects of lithium chloride using in vitro and in vivo models of cancer cachexia and sepsis. Lithium chloride prevented wasting in myotubes cultured with cancer cell-conditioned media, maintained the expression of the muscle fiber contractile protein, myosin heavy chain 2, and inhibited the upregulation of the E3 ubiquitin ligase, Atrogin-1. In addition, it inhibited the upregulation of inflammation-associated cytokines in macrophages treated with lipopolysaccharide. In the animal model of sepsis, lithium chloride treatment improved body weight, increased muscle mass, preserved the survival of larger fibers, and decreased the expression of muscle-wasting effector genes. In a model of cancer cachexia, lithium chloride increased muscle mass, enhanced muscle strength, and increased fiber cross-sectional area, with no significant effect on tumor mass. These results indicate that lithium chloride exerts therapeutic effects on inflammation-mediated skeletal muscle wasting, such as sepsis-induced muscle atrophy and cancer cachexia.

scholarly journals The Role of GSK-3β in the Regulation of Protein Turnover, Myosin Phenotype, and Oxidative Capacity in Skeletal Muscle under Disuse Conditions

2021 ◽  
Vol 22 (10) ◽  
pp. 5081
Author(s):  
Timur M. Mirzoev ◽  
Kristina A. Sharlo ◽  
Boris S. Shenkman
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Protein Turnover ◽  
Skeletal Muscles ◽  
Glycogen Synthase ◽  
Oxidative Capacity ◽  
The Body ◽  
Vital Functions ◽  
Wide Range ◽  
Gsk 3Β

Skeletal muscles, being one of the most abundant tissues in the body, are involved in many vital processes, such as locomotion, posture maintenance, respiration, glucose homeostasis, etc. Hence, the maintenance of skeletal muscle mass is crucial for overall health, prevention of various diseases, and contributes to an individual’s quality of life. Prolonged muscle inactivity/disuse (due to limb immobilization, mechanical ventilation, bedrest, spaceflight) represents one of the typical causes, leading to the loss of muscle mass and function. This disuse-induced muscle loss primarily results from repressed protein synthesis and increased proteolysis. Further, prolonged disuse results in slow-to-fast fiber-type transition, mitochondrial dysfunction and reduced oxidative capacity. Glycogen synthase kinase 3β (GSK-3β) is a key enzyme standing at the crossroads of various signaling pathways regulating a wide range of cellular processes. This review discusses various important roles of GSK-3β in the regulation of protein turnover, myosin phenotype, and oxidative capacity in skeletal muscles under disuse/unloading conditions and subsequent recovery. According to its vital functions, GSK-3β may represent a perspective therapeutic target in the treatment of muscle wasting induced by chronic disuse, aging, and a number of diseases.

scholarly journals Skeletal muscle wasting in chronic kidney disease: the emerging role of microRNAs

2019 ◽  
Vol 35 (9) ◽  
pp. 1469-1478 ◽  
Author(s):  
Kate A Robinson ◽  
Luke A Baker ◽  
Matthew P M Graham-Brown ◽  
Emma L Watson
Keyword(s):  
Skeletal Muscle ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Exciting Field ◽  
Skeletal Muscle Wasting ◽  
And Function

Abstract Skeletal muscle wasting is a common complication of chronic kidney disease (CKD), characterized by the loss of muscle mass, strength and function, which significantly increases the risk of morbidity and mortality in this population. Numerous complications associated with declining renal function and lifestyle activate catabolic pathways and impair muscle regeneration, resulting in substantial protein wasting. Evidence suggests that increasing skeletal muscle mass improves outcomes in CKD, making this a clinically important research focus. Despite extensive research, the pathogenesis of skeletal muscle wasting is not completely understood. It is widely recognized that microRNAs (miRNAs), a family of short non-coding RNAs, are pivotal in the regulation of skeletal muscle homoeostasis, with significant roles in regulating muscle growth, regeneration and metabolism. The abnormal expression of miRNAs in skeletal muscle during disease has been well described in cellular and animal models of muscle atrophy, and in recent years, the involvement of miRNAs in the regulation of muscle atrophy in CKD has been demonstrated. As this exciting field evolves, there is emerging evidence for the involvement of miRNAs in a beneficial crosstalk system between skeletal muscle and other organs that may potentially limit the progression of CKD. In this article, we describe the pathophysiological mechanisms of muscle wasting and explore the contribution of miRNAs to the development of muscle wasting in CKD. We also discuss advances in our understanding of miRNAs in muscle–organ crosstalk and summarize miRNA-based therapeutics currently in clinical trials.

Abstract 1432: Cardiomyocyte Myostatin Contributes to Skeletal Muscle Wasting in Heart Failure

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Joerg Heineke ◽  
Mannix Auger-Messier ◽  
Michelle Sargent ◽  
Allen York ◽  
Stephen Welle ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Precursor Protein ◽  
Mouse Serum ◽  
Skeletal Muscle Growth ◽  
Skeletal Muscle Wasting

Introduction: Skeletal muscle wasting during heart failure constitutes a major therapeutic challenge. The TGFβ superfamily member myostatin is a negative regulator of skeletal muscle growth. For example, elimination of myostatin (MSTN) in adult mice through an inducible Cre/lox recombination strategy has been shown to increase skeletal muscle mass by about 25%. Previous studies identified skeletal muscle and to a lesser extent cardiac and fat tissue as the source of MSTN production in the body. MSTN is produced as a precursor protein, which has been suggested to constitute the main reservoir of the protein in skeletal muscle. In mouse serum, however, MSTN is abundantly present in its mature form, which consists of the C-terminal fragment of the precursor protein. Results: We detected high levels of the mature MSTN protein (MM) in the mouse myocardium by western blotting. Interestingly, MM was significantly upregulated in the myocardium of mice subjected to long-term myocardial pressure overload (TAC, 12 weeks; protein levels: sham 100±22% vs. TAC 218±18%, p<0.01). In contrast, MM was barely detectable in mouse skeletal muscle. Immunhistochemical staining confirmed enhanced cardiomyocyte MSTN production after TAC. To determine the impact of cardiomyocyte MSTN on skeletal muscle growth during heart failure, we crossed cardiomyocyte specific Nkx2.5-Cre mice with mice in which the MSTN exon3 was flanked by loxp sites to eliminate expression of mature MSTN selectively in cardiomyocytes (CKO mice). While CKO mice did not have significant changes in skeletal muscle mass after a sham operation (e.g. quadriceps, normalized to tibia length: sham control 111±3.8 g/cm vs. sham CKO 106±4.3 g/cm), a 16% increase in skeletal muscle mass was observed in CKO mice after longterm TAC (quadriceps: TAC control 100±3.3 g/cm vs. TAC CKO 116±5.3 g/cm, p<0.05). In line with these results, mice with cardiomyocyte specific overexpression of MSTN (MSTN-Tg) showed a reduction in skeletal muscle mass (quadriceps: control 91±2.5 g/cm vs. MSTN-Tg 82±1.5 g/cm, p<0.05). Conclusion: Myocardial MSTN contributes to the development of skeletal muscle wasting in heart failure, most likely through an endocrine mechanism involving its secretion into the circulatory system.

scholarly journals The Toll-Like Receptor/MyD88/XBP1 Signaling Axis Mediates Skeletal Muscle Wasting during Cancer Cachexia

2019 ◽  
Vol 39 (15) ◽  
Author(s):  
Kyle R. Bohnert ◽  
Praneeth Goli ◽  
Anirban Roy ◽  
Aditya K. Sharma ◽  
Guangyan Xiong ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Active Form ◽  
Primary Response ◽  
Downstream Target ◽  
Tumor Bearing ◽  
Skeletal Muscle Wasting

ABSTRACT Skeletal muscle wasting causes both morbidity and mortality of cancer patients. Accumulating evidence suggests that the markers of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathways are increased in skeletal muscle under multiple catabolic conditions, including cancer. However, the signaling mechanisms and the role of individual arms of the UPR in the regulation of skeletal muscle mass remain largely unknown. In the present study, we demonstrated that gene expression of Toll-like receptors (TLRs) and myeloid differentiation primary response gene 88 (MyD88) was increased in skeletal muscle in a Lewis lung carcinoma (LLC) model of cancer cachexia. Targeted ablation of MyD88 inhibits the loss of skeletal muscle mass and strength in LLC tumor-bearing mice. Inhibition of MyD88 attenuates the LLC-induced activation of the UPR in skeletal muscle of mice. Moreover, muscle-specific deletion of X-box binding protein 1 (XBP1), a major downstream target of IRE1α arm of the UPR, ameliorates muscle wasting in LLC tumor-bearing mice. Our results also demonstrate that overexpression of an active form of XBP1 caused atrophy in cultured myotubes. In contrast, knockdown of XBP1 inhibits myotube atrophy in response to LLC or C26 adenocarcinoma cell conditioned medium. Collectively, our results demonstrate that TLR/MyD88-mediated activation of XBP1 causes skeletal muscle wasting in LLC tumor-bearing mice.

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