Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway

Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular dystrophy. As a publicly recognized strategy for extending lifespan and improving the health of the elderly, the underlying mechanisms of lifelong regular aerobic exercise for the prevention of sarcopenia have not been fully elucidated. To explore the role of lifelong aerobic exercise in the beneficial regulation of autophagic signaling pathways in senescent skeletal muscle, the natural aging mice were used as the sarcopenia model and subjected to lifelong treadmill running to evaluate corresponding parameters related to skeletal muscle atrophy and autophagic signaling pathways. Compared with the young control mice, the aged mice showed a significant reduction in skeletal muscle mass, gastrocnemius muscle weight/body weight (GMW/BW) ratio, and cross-sectional areas (CSA) of skeletal muscle fibers (p < 0.01). In contrast, lifelong aerobic exercise effectively rescued these reduced biomarkers associated with muscle atrophy. Moreover, as shown in the activated AMPK/PGC-1α signaling pathway, lifelong aerobic exercise successfully prevented the aging-induced impairment of the ubiquitin-proteasome system (UPS), excessive apoptosis, defective autophagy, and mitochondrial dysfunction. The exercise-induced autophagy suppressed the key regulatory components of the UPS, inhibited excessive apoptosis, and optimized mitochondrial quality control, thereby preventing and delaying aging-induced skeletal muscle atrophy.

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Edward F. Adolph Distinguished Lecture. Skeletal muscle atrophy: Multiple pathways leading to a common outcome

Journal of Applied Physiology ◽

10.1152/japplphysiol.00381.2020 ◽

2020 ◽

Vol 129 (2) ◽

pp. 272-282 ◽

Cited By ~ 3

Author(s):

Sue C. Bodine

Keyword(s):

Skeletal Muscle ◽

Signaling Pathways ◽

Muscle Mass ◽

Muscle Atrophy ◽

Skeletal Muscle Mass ◽

Single Gene ◽

Skeletal Muscle Atrophy ◽

Protein Breakdown ◽

E3 Ligases ◽

The Past

Skeletal muscle atrophy continues to be a serious consequence of many diseases and conditions for which there is no treatment. Our understanding of the mechanisms regulating skeletal muscle mass has improved considerably over the past two decades. For many years it was known that skeletal muscle atrophy resulted from an imbalance between protein synthesis and protein breakdown, with the net balance shifting toward protein breakdown. However, the molecular and cellular mechanisms underlying the increased breakdown of myofibrils was unknown. Over the past two decades, numerous reports have identified novel genes and signaling pathways that are upregulated and activated in response to stimuli such as disuse, inflammation, metabolic stress, starvation and others that induce muscle atrophy. This review summarizes the discovery efforts performed in the identification of several pathways involved in the regulation of skeletal muscle mass: the mammalian target of rapamycin (mTORC1) and the ubiquitin proteasome pathway and the E3 ligases, MuRF1 and MAFbx. While muscle atrophy is a common outcome of many diseases, it is doubtful that a single gene or pathway initiates or mediates the breakdown of myofibrils. Interestingly, however, is the observation that upregulation of the E3 ligases, MuRF1 and MAFbx, is a common feature of many divergent atrophy conditions. The challenge for the field of muscle biology is to understand how all of the various molecules, transcription factors, and signaling pathways interact to produce muscle atrophy and to identify the critical factors for intervention.

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Swim training affects Akt signaling and ameliorates loss of skeletal muscle mass in a mouse model of amyotrophic lateral sclerosis

Scientific Reports ◽

10.1038/s41598-021-00319-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Karol Cieminski ◽

Damian Jozef Flis ◽

Katarzyna Dzik ◽

Jan Jacek Kaczor ◽

Emilia Czyrko ◽

...

Keyword(s):

Skeletal Muscle ◽

Signaling Pathway ◽

Muscle Mass ◽

Muscle Atrophy ◽

Skeletal Muscle Mass ◽

Tibialis Anterior Muscle ◽

Akt Signaling ◽

The Body ◽

Skeletal Muscle Atrophy ◽

Akt Signaling Pathway

AbstractWe tested the hypothesis that swim training reverses the impairment of Akt/FOXO3a signaling, ameliorating muscle atrophy in ALS mice. Transgenic male mice B6SJL-Tg (SOD1G93A) 1Gur/J were used as the ALS model (n = 35), with wild-type B6SJL (WT) mice as controls (n = 7). ALS mice were analyzed before ALS onset, at ALS onset, and at terminal ALS. Levels of insulin/Akt signaling pathway proteins were determined, and the body and tibialis anterior muscle mass and plasma creatine kinase. Significantly increased levels of FOXO3a in ALS groups (from about 13 to 21-fold) compared to WT mice were observed. MuRF1 levels in the ONSET untrained group (12.0 ± 1.7 AU) were significantly higher than in WT mice (1.12 ± 0.2 AU) and in the BEFORE ALS group (3.7 ± 0.9 AU). This was associated with body mass and skeletal muscle mass reduction. Swim training significantly ameliorated the reduction of skeletal muscle mass in both TERMINAL groups (p < 0.001) and partially reversed changes in the levels of Akt signaling pathway proteins. These findings shed light on the swimming-induced attenuation of skeletal muscle atrophy in ALS with possible practical implications for anti-cachexia approaches.

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Expression Levels of Long Non-Coding RNAs Change in Models of Altered Muscle Activity and Muscle Mass

International Journal of Molecular Sciences ◽

10.3390/ijms21051628 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1628 ◽

Cited By ~ 3

Author(s):

Keisuke Hitachi ◽

Masashi Nakatani ◽

Shiori Funasaki ◽

Ikumi Hijikata ◽

Mizuki Maekawa ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Muscle Atrophy ◽

Skeletal Muscle Mass ◽

Muscle Size ◽

Skeletal Muscle Atrophy ◽

Myostatin Gene ◽

Expression Levels ◽

Non Coding Rnas

Skeletal muscle is a highly plastic organ that is necessary for homeostasis and health of the human body. The size of skeletal muscle changes in response to intrinsic and extrinsic stimuli. Although protein-coding RNAs including myostatin, NF-κβ, and insulin-like growth factor-1 (IGF-1), have pivotal roles in determining the skeletal muscle mass, the role of long non-coding RNAs (lncRNAs) in the regulation of skeletal muscle mass remains to be elucidated. Here, we performed expression profiling of nine skeletal muscle differentiation-related lncRNAs (DRR, DUM1, linc-MD1, linc-YY1, LncMyod, Neat1, Myoparr, Malat1, and SRA) and three genomic imprinting-related lncRNAs (Gtl2, H19, and IG-DMR) in mouse skeletal muscle. The expression levels of these lncRNAs were examined by quantitative RT-PCR in six skeletal muscle atrophy models (denervation, casting, tail suspension, dexamethasone-administration, cancer cachexia, and fasting) and two skeletal muscle hypertrophy models (mechanical overload and deficiency of the myostatin gene). Cluster analyses of these lncRNA expression levels were successfully used to categorize the muscle atrophy models into two sub-groups. In addition, the expression of Gtl2, IG-DMR, and DUM1 was altered along with changes in the skeletal muscle size. The overview of the expression levels of lncRNAs in multiple muscle atrophy and hypertrophy models provides a novel insight into the role of lncRNAs in determining the skeletal muscle mass.

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Activation of the vasoactive intestinal peptide 2 receptor modulates normal and atrophying skeletal muscle mass and force

Journal of Applied Physiology ◽

10.1152/japplphysiol.00736.2004 ◽

2005 ◽

Vol 98 (2) ◽

pp. 655-662 ◽

Cited By ~ 11

Author(s):

Richard T. Hinkle ◽

Elizabeth Donnelly ◽

David B. Cody ◽

Russell J. Sheldon ◽

Robert J. Isfort

Keyword(s):

Skeletal Muscle ◽

Vasoactive Intestinal Peptide ◽

Muscle Mass ◽

Muscle Atrophy ◽

Skeletal Muscle Mass ◽

Skeletal Muscle Atrophy ◽

Physiological Control ◽

Corticosteroid Administration ◽

Skeletal Muscle Wasting ◽

Selective Agonist

Of the two known vasoactive intestinal peptide receptors (VPAC1R and VPAC2R), the VPAC2R is expressed in skeletal muscle. To evaluate the function of the VPAC2R in the physiological control of skeletal muscle mass, we utilized the VPAC1R selective agonist [K15,R16,L27]VIP(1-7) GRF(8-27)-NH2 and the VPAC2R selective agonist Ro-25-1553 to treat mice and rats undergoing either nerve damage-, corticosteroid-, or disuse-induced skeletal muscle atrophy. These analyses demonstrated that activation of VPAC2R, but not VPAC1R, reduced the loss of skeletal muscle mass and force during conditions of skeletal muscle atrophy resulting from corticosteroid administration, denervation, casting-induced disuse, increased skeletal muscle mass, and force of nonatrophying muscles. These studies indicate that VPAC2R agonists may have utility for the treatment of skeletal muscle-wasting diseases.

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Functional rice with tandemly repeated Cbl-b ubiquitin ligase inhibitory pentapeptide prevents denervation-induced muscle atrophy in vivo

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbab059 ◽

2021 ◽

Author(s):

Kazuhito Akama ◽

Yasuka Shimajiri ◽

Kumiko Kainou ◽

Ryota Iwasaki ◽

Reiko Nakao ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Transgenic Rice ◽

Muscle Atrophy ◽

Ubiquitin Ligase ◽

Critical Role ◽

Phosphorylation Site ◽

Skeletal Muscle Atrophy ◽

Rice Seeds

Abstract Ubiquitin ligase Cbl-b play a critical role in non-loading-mediated skeletal muscle atrophy: Cbl-b ubiquitinates insulin receptor substrate-1 (IRS-1), an important insulin-like growth factor-1 signaling intermediate molecule, leading to its degradation and a resulting loss in muscle mass. We reported that intramuscular injection of a pentapeptide, DGpYMP, which acts as a mimic of the phosphorylation site in IRS-1, significantly inhibited denervation-induced skeletal muscle loss. In order to explore the possibility of the prevention of muscle atrophy by diet therapy, we examined the effects of oral administration of transgenic rice containing Cblin (Cbl-b inhibitor) peptide (DGYMP) on denervation-induced muscle mass loss in frogs. We generated transgenic rice seeds in which 15 repeats of Cblin peptides with a WQ spacer were inserted into the rice storage protein glutelin for expression. A diet of the transgenic rice seeds had significant inhibitory effects on denervation-induced atrophy of the leg skeletal muscles in frogs, compared with those receiving a diet of wild-type rice.

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Tail suspension is useful as a sarcopenia model in rats

Laboratory Animal Research ◽

10.1186/s42826-020-00083-9 ◽

2021 ◽

Vol 37 (1) ◽

Author(s):

Akira Nemoto ◽

Toru Goyagi

Keyword(s):

Skeletal Muscle ◽

Muscle Contraction ◽

Experimental Model ◽

Muscle Mass ◽

Muscle Atrophy ◽

Whole Body ◽

Skeletal Muscle Atrophy ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Simple Method

Abstract Background Sarcopenia promotes skeletal muscle atrophy and exhibits a high mortality rate. Its elucidation is of the highest clinical importance, but an animal experimental model remains controversial. In this study, we investigated a simple method for studying sarcopenia in rats. Results Muscle atrophy was investigated in 24-week-old, male, tail-suspended (TS), Sprague Dawley and spontaneously hypertensive rats (SHR). Age-matched SD rats were used as a control group. The skeletal muscle mass weight, muscle contraction, whole body tension (WBT), cross-sectional area (CSA), and Muscle RING finger-1 (MuRF-1) were assessed. Enzyme-linked immunosorbent assay was used to evaluate the MuRF-1 levels. Two muscles, the extensor digitorum longus and soleus muscles, were selected for representing fast and slow muscles, respectively. All data, except CSA, were analyzed by a one-way analysis of variance, whereas CSA was analyzed using the Kruskal-Wallis test. Muscle mass weight, muscle contraction, WBT, and CSA were significantly lower in the SHR (n = 7) and TS (n = 7) groups than in the control group, whereas MuRF-1 expression was dominant. Conclusions TS and SHR presented sarcopenic phenotypes in terms of muscle mass, muscle contraction and CSA. TS is a useful technique for providing muscle mass atrophy and weakness in an experimental model of sarcopenia in rats.

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Aerobic exercise and resistance exercise alleviate skeletal muscle atrophy through IGF-1/IGF-1R-PI3K/Akt pathway in mice with myocardial infarction

AJP Cell Physiology ◽

10.1152/ajpcell.00344.2021 ◽

2021 ◽

Author(s):

Feng Li-Li ◽

Li Bo-Wen ◽

Xi Yue ◽

Tian Zhen-Jun ◽

Cai Meng-Xin

Keyword(s):

Myocardial Infarction ◽

Skeletal Muscle ◽

Protein Synthesis ◽

Resistance Exercise ◽

Aerobic Exercise ◽

Muscle Atrophy ◽

Cell Apoptosis ◽

Exercise Group ◽

Skeletal Muscle Atrophy ◽

Akt Pathway

Objectives: Myocardial infarction (MI)-induced heart failure (HF) is commonly accompanied with profound effects on skeletal muscle. With the process of MI-induced HF, perturbations in skeletal muscle contribute to muscle atrophy. Exercise is viewed as a feasible strategy to prevent muscle atrophy. The aims of this study were to investigate whether exercise could alleviate MI-induced skeletal muscle atrophy via insulin-like growth factor 1 (IGF-1) pathway in mice. Materials and Methods: Male C57/BL6 mice were used to establish the MI model and divided into three groups: sedentary MI group, MI with aerobic exercise group and MI with resistance exercise group, sham-operated group was used as control. Exercise-trained animals were subjected to four-weeks of aerobic exercise (AE) or resistance exercise (RE). Cardiac function, muscle weight, myofiber size, levels of IGF-1 signaling and proteins related to myogenesis, protein synthesis and degradation and cell apoptosis in gastrocnemius muscle were detected. And H2O2-treated C2C12 cells were intervened with recombinant human IGF-1, IGF-1R inhibitor NVP-AEW541 and PI3K inhibitor LY294002 to explore the mechanism. Results：Exercises up-regulated the IGF-1/IGF-1R-phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling, increased the expressions of Pax7, myogenic regulatory factors (MRFs) and protein synthesis, reduced protein degradation and cell apoptosis in MI-mice. In vitro, IGF-1 up-regulated the levels of Pax7 and MRFs, mTOR and P70S6K, reduced MuRF1, MAFbx and inhibited cell apoptosis via IGF-1R-PI3K/Akt pathway. Conclusion: AE and RE, safely and effectively, alleviate skeletal muscle atrophy by regulating the levels of myogenesis, protein degradation and cells apoptosis in mice with MI via activating IGF-1/IGF-1R-PI3K/Akt pathway.

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