Attenuation of autophagy impacts on muscle fibre development, starvation induced stress and fibre regeneration following acute injury

Paolini, Andrea; Omairi, Saleh; Mitchell, Robert D.; Vaughan, Danielle; Matsakas, Antonios; Vaiyapuri, Sakthivel; Ricketts, Thomas C.; Rubinsztein, David C.; Patel, Ketan

doi:10.1038/s41598-018-27429-7

Cited by 37 publications

(36 citation statements)

References 53 publications

(22 reference statements)

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“…Similarly, mice treated with hydroxy chloroquine (CQ), another chemical inhibitor of autophagy, perturbs muscle regeneration and exacerbates the pathology of mdx mice [44]. Genetic inhibition of autophagy through whole body knockdown of Atg16 results in impaired regeneration following cardiotoxin-induced injury [45]. While the importance of autophagy in the regenerative programs have been shown largely using whole body blockage of autophagy, limited investigation has focused on myofiber-specific manipulation of autophagy.…”

Section: Autophagy Effects On Skeletal Muscle Homeostasis Regenermentioning

confidence: 99%

Autophagy as a Therapeutic Target to Enhance Aged Muscle Regeneration

Lee

Bareja

Bartlett

et al. 2019

Cells

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Skeletal muscle has remarkable regenerative capacity, relying on precise coordination between resident muscle stem cells (satellite cells) and the immune system. The age-related decline in skeletal muscle regenerative capacity contributes to the onset of sarcopenia, prolonged hospitalization, and loss of autonomy. Although several age-sensitive pathways have been identified, further investigation is needed to define targets of cellular dysfunction. Autophagy, a process of cellular catabolism, is emerging as a key regulator of muscle regeneration affecting stem cell, immune cell, and myofiber function. Muscle stem cell senescence is associated with a suppression of autophagy during key phases of the regenerative program. Macrophages, a key immune cell involved in muscle repair, also rely on autophagy to aid in tissue repair. This review will focus on the role of autophagy in various aspects of the regenerative program, including adult skeletal muscle stem cells, monocytes/macrophages, and corresponding age-associated dysfunction. Furthermore, we will highlight rejuvenation strategies that alter autophagy to improve muscle regenerative function.

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Section: Autophagy Effects On Skeletal Muscle Homeostasis Regenermentioning

confidence: 99%

Autophagy as a Therapeutic Target to Enhance Aged Muscle Regeneration

Lee

Bareja

Bartlett

et al. 2019

Cells

View full text Add to dashboard Cite

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“…Nevertheless, some intracellular mechanisms critical for muscle regeneration have recently been identified. For example, autophagy, a key homeostatic process necessary for degradation of unwanted cellular components, plays a crucial role in successful muscle regeneration after injury (Call et al, 2017;Garcia-Prat et al, 2016;Paolini et al, 2018). Again, however, molecules that regulate autophagy during regeneration are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

ARHGEF3 regulates skeletal muscle regeneration and strength through autophagy

You

Singh

Reyes-Ordoñez

et al. 2020

Preprint

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Skeletal muscle regeneration is essential for restoring muscle function upon injury and for the maintenance of muscle health with aging. ARHGEF3, a Rho-specific GEF, negatively regulates myoblast differentiation via mammalian target of rapamycin complex 2 (mTORC2)-Akt signaling in a GEF-independent manner in vitro. Here, we investigated ARHGEF3's role in skeletal muscle regeneration by creating ARHGEF3 KO mice. These mice exhibited no discernible phenotype under normal conditions. Upon injury, however, ARHGEF3 deficiency enhanced the mass, fiber size and function of regenerating muscles in both young and aged mice. Surprisingly, these effects were not mediated by mTORC2-Akt signaling, but by the GEF activity of ARHGEF3. Furthermore, ARHGEF3 KO promoted muscle regeneration through activation of autophagy, a process that is also critical for maintaining muscle strength.Accordingly, in old mice, ARHGEF3 depletion prevented muscle weakness by restoring autophagy flux. Collectively, our findings identify an unexpected link between ARHGEF3 and autophagy-related muscle pathophysiology.

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“…Total RNA was isolated from both cells and tissue as described previously, by using the standard TRIzol method (AMRESCO RiboZol TM RNA Extraction Reagent) using the EZNA total RNA kit I (Omega Bio‐Tek). Briefly, RNA was purified by DNase I treatment (Roche).…”

Section: Methodsmentioning

confidence: 99%

Loss of CD36 protects against diet‐induced obesity but results in impaired muscle stem cell function, delayed muscle regeneration and hepatic steatosis

et al. 2019

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Aim The prevalence of obesity is a major risk factor for cardiovascular and metabolic diseases including impaired skeletal muscle regeneration. Since skeletal muscle regenerative capacity is regulated by satellite cells, we aimed to investigate whether a high‐fat diet impairs satellite cell function and whether this is linked to fatty acid uptake via CD36. We also aimed to determine whether loss of CD36 impacts on muscle redox homeostasis and skeletal muscle regenerative capacity. Methods We studied the impact of a high‐fat diet and CD36 deficiency on murine skeletal muscle morphology, redox homeostasis, satellite cell function, bioenergetics and lipid accumulation in the liver. We also determined the effect of CD36 deficiency on skeletal muscle regeneration. Results High‐fat diet increased body weight, intramuscular lipid accumulation and oxidative stress in wild‐type mice that were significantly mitigated in CD36‐deficient mice. High‐fat diet and CD36 deficiency independently attenuated satellite cell function on single fibres and myogenic capacity on primary satellite cells. CD36 deficiency resulted in delayed skeletal muscle regeneration following acute injury with cardiotoxin. CD36‐deficient and wild‐type primary satellite cells had distinct bioenergetic profiles in response to palmitate. High‐fat diet induced hepatic steatosis in both genotypes that was more pronounced in the CD36‐deficient mice. Conclusion This study demonstrates that CD36 deficiency protects against diet‐induced obesity, intramuscular lipid deposition and oxidative stress but results in impaired muscle satellite cell function, delayed muscle regeneration and hepatic steatosis. CD36 is a key mediator of fatty acid uptake in skeletal muscle, linking obesity with satellite cell function and muscle regeneration.

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Attenuation of autophagy impacts on muscle fibre development, starvation induced stress and fibre regeneration following acute injury

Cited by 37 publications

References 53 publications

Autophagy as a Therapeutic Target to Enhance Aged Muscle Regeneration

Autophagy as a Therapeutic Target to Enhance Aged Muscle Regeneration

ARHGEF3 regulates skeletal muscle regeneration and strength through autophagy

Loss of CD36 protects against diet‐induced obesity but results in impaired muscle stem cell function, delayed muscle regeneration and hepatic steatosis

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