mTOR regulates skeletal muscle regeneration in vivo through kinase-dependent and kinase-independent mechanisms

Ge, Yejing; Wu, Ai-Luen; Warnes, Christine; Liu, Jianming; Zhang, Chongben; Kawasome, Hideki; Terada, Naohiro; Boppart, Marni D.; Schoenherr, Christopher J.; Chen, Jiawen

doi:10.1152/ajpcell.00248.2009

Cited by 117 publications

(160 citation statements)

References 39 publications

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“…This suggests a difference between the patterns of mTOR activation in TA versus Dia muscles of mdx mice. This is a novel finding that contributes to our understanding of the differences in function and progression of pathology between Dia and limb muscle of mdx mice (38)(39)(40).…”

Section: Discussionmentioning

confidence: 84%

Rapamycin Ameliorates Dystrophic Phenotype in mdx Mouse Skeletal Muscle

Eghtesad

Jhunjhunwala

Little

et al. 2011

Mol Med

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Duchenne muscular dystrophy (DMD) is an X-linked, lethal, degenerative disease that results from mutations in the dystrophin gene, causing necrosis and inflammation in skeletal muscle tissue. Treatments that reduce muscle fiber destruction and immune cell infiltration can ameliorate DMD pathology. We treated the mdx mouse, a model for DMD, with the immunosuppressant drug rapamycin (RAPA) both locally and systemically to examine its effects on dystrophic mdx muscles. We observed a significant reduction of muscle fiber necrosis in treated mdx mouse tibialis anterior (TA) and diaphragm (Dia) muscles 6 wks post-treatment. This effect was associated with a significant reduction in infiltration of effector CD4 + and CD8 + T cells in skeletal muscle tissue, while Foxp3 + regulatory T cells were preserved. Because RAPA exerts its effects through the mammalian target of RAPA (mTOR), we studied the activation of mTOR in mdx TA and Dia with and without RAPA treatment. Surprisingly, mTOR activation levels in mdx TA were not different from control C57BL/10 (B10). However, mTOR activation was different in Dia between mdx and B10; mTOR activation levels did not rise between 6 and 12 wks of age in mdx Dia muscle, whereas a rise in mTOR activation level was observed in B10 Dia muscle. Furthermore, mdx Dia, but not TA, muscle mTOR activation was responsive to RAPA treatment.

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Section: Discussionmentioning

confidence: 84%

Rapamycin Ameliorates Dystrophic Phenotype in mdx Mouse Skeletal Muscle

Eghtesad

Jhunjhunwala

Little

et al. 2011

Mol Med

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“…To gain insight into the function of Flt3L in vivo, we employed a skeletal muscle regeneration model in which muscle necrosis induced by barium chloride (BaCl 2 ) was followed by a welldefined process of regeneration (Ge et al, 2009). When RNA was extracted from injected tibialis anterior (TA) muscles and subjected to qPCR analysis, Flt3L mRNA level was found to increase modestly on day 5 post-injury and return to the basal level by day 7 (Fig.…”

Section: Flt3l Is Involved In Muscle Regeneration In Vivomentioning

confidence: 99%

“…Muscle injury was induced by injection of BaCl 2 (50 ml of 1.2% w/v in saline) into TA muscles as previously described (Ge et al, 2009). On various days after injury, the mice were euthanized, and the TA muscles were collected, followed by RNA extraction, or cryosectioning and staining as described in the next section.…”

Section: Muscle Injury Regeneration and Flt3l Knockdown In Micementioning

confidence: 99%

Flt3L is a novel regulator of skeletal myogenesis

Waldemer

Nalluri

et al. 2013

Journal of Cell Science

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SummaryVarious cues initiate multiple signaling pathways to regulate the highly coordinated process of skeletal myogenesis. Myoblast differentiation comprises a series of ordered events starting with cell cycle withdrawal and ending with myocyte fusion, with each step probably controlled by multiple extracellular signals and intracellular signaling pathways. Here we report the identification of Fms-like tyrokine kinase 3 ligand (Flt3L) signaling as a novel regulator of skeletal myogenesis. Flt3L is a multifunctional cytokine in immune cells, but its involvement in skeletal muscle formation has not been reported. We found that Flt3L is expressed in C2C12 myoblasts, with levels increasing throughout differentiation. Knockdown of Flt3L, or its receptor Flt3, suppresses myoblast differentiation, which is rescued by recombinant Flt3L or Flt3, respectively. Differentiation is not rescued, however, by recombinant ligand when the receptor is knocked down, or vice versa, suggesting that Flt3L and Flt3 function together. Flt3L knockdown also inhibits differentiation in mouse primary myoblasts. Both Flt3L and Flt3 are highly expressed in nascent myofibers during muscle regeneration in vivo, and Flt3L siRNA impairs muscle regeneration, validating the physiological significance of Flt3L function in myogenesis. We have identified a cellular mechanism for the myogenic function of Flt3L, as we show that Flt3L promotes cell cycle exit that is necessary for myogenic differentiation. Furthermore, we identify Erk as a relevant target of Flt3L signaling during myogenesis, and demonstrate that Flt3L suppresses Erk signaling through p120RasGAP. In summary, our work reveals an unexpected role for an immunoregulatory cytokine in skeletal myogenesis and a new myogenic pathway.

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“…However, in the setting of muscle injury, this comes at a cost, as mTOR/AKT signaling regulates myofiber size (2,30). Previous studies that shown that, while the early phases of muscle regeneration proceed with rapamycin, myofiber growth is halted (38). Separately, BMP through type I receptor activity has been shown to positively regulate muscle size (3)(4)(5).…”

Section: Discussionmentioning

confidence: 99%