Disrupted autophagy undermines skeletal muscle adaptation and integrity

Jokl, Elliot; Blanco, Gonzalo

doi:10.1007/s00335-016-9659-2

Cited by 33 publications

(26 citation statements)

References 121 publications

(164 reference statements)

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“…Furthermore, similar to our observations, another investigation found that 8 weeks of resistance ladder training under normoxia reduces the LC3II/LC3I ratio and elevates the level of p62 [42]. Thus, regular long-term repetitive training may increase the threshold for activation of autophagy by stress, thereby protecting the muscle [43][44][45].…”

Section: Resistance Training Alleviates Hypoxia-induced Muscle Atrophsupporting

confidence: 86%

Resistance Training Alleviates Skeletal Muscle Atrophy in Rats Exposed to Hypoxia by inhibiting Autophagy Mediated by Acetyl-FoxO1

Fu¹,

Kong²,

Lijing³

et al. 2020

Preprint

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Background: Skeletal muscle atrophy induced by hypoxia could affect the physical fitness and training effect of the athletes in the rapid altitude, and also affect the production and life of the general public. Resistance training in a hypoxic environment could effectively alleviate the occurrence of muscular atrophy. Whether autophagy lysosomal pathway, as an important proteolysis pathway, is involved in this process, and whether FoxO1, the key gene of atrophy, plays a role by regulating autophagy is unclear. Methods: Male Sprague-Dawley (SD) rats were randomly divided into normoxic control group (group C), normoxic resistance-training group (group R), hypoxic control group (group H), and hypoxic resistance-training group (group HR). The H and HR groups were exposed to 12.4% oxygen for four weeks. The R and HR groups underwent incremental loaded training by climbing a ladder every other day for four weeks. Results: Compared to parameters in group H, resistance training increased lean body mass (LBM) and wet weight and decreased the expression of atrogin1 of the extensor digitorum longus (EDL) after four weeks ( P <0.05). Resistance training decreased the levels of FoxO1 and Ac-FoxO1 and the extent of their localization in the nucleus and cytoplasm, respectively ( P <0.05), as well as the LC3II/LC3I ratio, the integrated optical density (IOD) of LC3 and the levels of autophagy-related gene 7 (Atg7), and elevated the levels of sequestosome 1 (SQSTM1/p62) ( P <0.05). Most differentially expressed autophagy-related genes (ATGs) interacted with FoxO1, and the functions of these ATGs were mainly enriched in the early autophagy phase. Conclusions: Our findings demonstrate that resistance training lowers the levels of both nuclear FoxO1 and cytoplasmic Ac-FoxO1, as well as reduced autophagic flux in the EDL of rats exposed to hypoxia.

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Section: Resistance Training Alleviates Hypoxia-induced Muscle Atrophsupporting

confidence: 86%

Resistance Training Alleviates Skeletal Muscle Atrophy in Rats Exposed to Hypoxia by inhibiting Autophagy Mediated by Acetyl-FoxO1

Fu¹,

Kong²,

Lijing³

et al. 2020

Preprint

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“…Autophagy plays an important function in skeletal muscle maintenance by regulating protein homeostasis, and impaired autophagy disrupts the fitness and integrity of skeletal muscles [26]. We found that CSRP3 regulates basal autophagy and exerts a beneficial role in chicken primary myoblasts.…”

Section: Discussionmentioning

confidence: 79%

The Autophagy Regulatory Molecule CSRP3 Interacts with LC3 and Protects Against Muscular Dystrophy

Cui

Han

Tang

et al. 2020

IJMS

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CSRP3/MLP (cysteine-rich protein 3/muscle Lim protein), a member of the cysteine-rich protein family, is a muscle-specific LIM-only factor specifically expressed in skeletal muscle. CSRP3 is critical in maintaining the structure and function of normal muscle. To investigate the mechanism of disease in CSRP3 myopathy, we performed siRNA-mediated CSRP3 knockdown in chicken primary myoblasts. CSRP3 silencing resulted in the down-regulation of the expression of myogenic genes and the up-regulation of atrophy-related gene expressions. We found that CSRP3 interacted with LC3 protein to promote the formation of autophagosomes during autophagy. CSRP3-silencing impaired myoblast autophagy, as evidenced by inhibited autophagy-related ATG5 and ATG7 mRNA expression levels, and inhibited LC3II and Beclin-1 protein accumulation. In addition, impaired autophagy in CSRP3-silenced cells resulted in increased sensitivity to apoptosis cell death. CSRP3-silenced cells also showed increased caspase-3 and caspase-9 cleavage. Moreover, apoptosis induced by CSRP3 silencing was alleviated after autophagy activation. Together, these results indicate that CSRP3 promotes the correct formation of autophagosomes through its interaction with LC3 protein, which has an important role in skeletal muscle remodeling and maintenance.

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“…In healthy cells potentially harmful cellular contents such as protein aggregates or damaged organelles are eliminated by selective autophagy. Defective autophagic processes result in poor protein quality control, limited availability of free amino acids, disrupted metabolic homeostasis and inefficient stress response triggering compensatory mechanisms that lead to excess autophagy (38). Altered, upregulated autophagy involves a decline in the selectiveness of this process that now takes place in an indiscriminate manner (16), in line with the phenotype of vacuolar myopathies.…”

Section: Discussionmentioning

confidence: 99%

“…In these disorders, normal, tightly regulated autophagy is disturbed, leading to the accumulation of autophagic substrate in large, membrane‐bound vacuoles. Muscle fibers are particularly susceptible to alterations of autophagy, because they constantly accumulate autophagic substrate caused by high protein turnover and exposure to mechanical stress (38). In addition, dysfunctional mitochondria that undergo mitophagy accumulate at high numbers in muscle fibers during aging (18).…”

Section: Discussionmentioning

confidence: 99%

“…Typical genetic causes include deficiencies in lysosomal enzymes. These defects disturb the lysosomal pathway which is a key element of the autophagy machinery (70), exemplified by glycogen storage disease II (GSD II; Pompe disease) caused by lysosomal alpha glucosidase deficiency, Danon disease caused by mutation of the lysosomal membrane receptor LAMP2 and X‐linked myopathy with excessive autophagy (XMEA) caused by mutation of the a V‐ATPase lysosomal proton channel (9,38).…”

Section: Introductionmentioning

confidence: 99%

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Differential diagnosis of vacuolar myopathies in the NGS era

et al. 2020

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Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non‐inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late‐onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE, LDB3/ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy (FKRP, DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr‐caveolinopathy and of limb‐girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.

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Disrupted autophagy undermines skeletal muscle adaptation and integrity

Cited by 33 publications

References 121 publications

Resistance Training Alleviates Skeletal Muscle Atrophy in Rats Exposed to Hypoxia by inhibiting Autophagy Mediated by Acetyl-FoxO1

Resistance Training Alleviates Skeletal Muscle Atrophy in Rats Exposed to Hypoxia by inhibiting Autophagy Mediated by Acetyl-FoxO1

The Autophagy Regulatory Molecule CSRP3 Interacts with LC3 and Protects Against Muscular Dystrophy

Differential diagnosis of vacuolar myopathies in the NGS era

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