Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo

  title={Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo},
  author={Sue C. Bodine and Trevor Stitt and Michael Gonzalez and William O. Kline and Gretchen L. Stover and Roy Bauerlein and Elizabeth Zlotchenko and Angus G. Scrimgeour and John C. Lawrence and David J. Glass and George D. Yancopoulos},
  journal={Nature Cell Biology},
Skeletal muscles adapt to changes in their workload by regulating fibre size by unknown mechanisms. [] Key Method The roles of two signalling pathways implicated in muscle hypertrophy on the basis of findings in vitro, Akt/mTOR (mammalian target of rapamycin) and calcineurin/NFAT (nuclear factor of activated T cells), were investigated in several models of skeletal muscle hypertrophy and atrophy in vivo. The Akt/mTOR pathway was upregulated during hypertrophy and downregulated during muscle atrophy…

Akt1 deficiency diminishes skeletal muscle hypertrophy by reducing satellite cell proliferation.

Observations suggest that the load-induced activation of mTOR signaling occurs independently of Akt1 regulation and thatAkt1 plays a critical role in regulating satellite cell proliferation during load- induced muscle hypertrophy.

mTORC1 Promotes Denervation-Induced Muscle Atrophy Through a Mechanism Involving the Activation of FoxO and E3 Ubiquitin Ligases

It is found that at later stages after denervation of fast-twitch muscle, activation of mTORC1 contributed to atrophy and that denervation-induced atrophy was mitigated by inhibition of m TORC1 with rapamycin, which represents a potential therapeutic target in neurogenic muscle atrophy.

Transient activation of mTORC1 signaling in skeletal muscle is independent of Akt1 regulation

Observations show that the upstream IGF‐1/Akt1 regulation is dispensable for the acute activation of mTORC1 signaling and regulation of satellite cells in response to mechanical overload.

Involvement of PI3K/Akt/TOR pathway in stretch‐induced hypertrophy of myotubes

It is found that cyclic stretching of myotubes activates the PI3K/Akt/TOR pathway, resulting in musclehypertrophy, and the MEK/ERK pathway may contribute negatively to spontaneous hypertrophy.

The missing Akt in the mechanical regulation of skeletal muscle mTORC1 signalling and growth

Miyazaki and colleagues demonstrate in vivo that early mTORC1 activation and muscle growth following mechanical overload in C57BL/6J mice is also independent of IGF-1/PI3K/Akt signalling, the first evidence in skeletal muscle indicating that MEK/ERK signalling can regulate m TORC1 activity by phosphorylating TSC2 at the serine 664 site.

Mechanotransduction pathways in skeletal muscle hypertrophy

This point-of-view paper is to highlight mechanotransduction events, with focus on the mechanisms of mTORC1 and PA activation, and the role of IGF-1 on hypertrophy process.

PI3 kinase regulation of skeletal muscle hypertrophy and atrophy.

  • D. Glass
  • Biology
    Current topics in microbiology and immunology
  • 2010
Findings show that myostatin signaling acts by blocking genes induced during differentiation, even in a myotube, as opposed to activating the distinct "atrophy program," which is implicated most prominently downstream of Insulin-like growth factor 1 signaling.



Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways

It is shown that Akt promotes hypertrophy by activating downstream signalling pathways previously implicated in activating protein synthesis: the pathways downstream of mammalian target of rapamycin (mTOR) and the pathway activated by phosphorylating and thereby inhibiting glycogen synthase kinase 3 (GSK3).

Skeletal muscle hypertrophy is mediated by a Ca2+-dependent calcineurin signalling pathway

It is proposed that growth-factor-induced skeletal-muscle hypertrophy and changes in myofibre phenotype are mediated by calcium mobilization and are critically regulated by the calcineurin/NF-ATc1 signalling pathway.

Calcineurin Is Required for Skeletal Muscle Hypertrophy*

Administration of the specific calcineurin inhibitors cyclosporin (CsA) or FK506 to mice prevented the rapid doubling of mass and individual fiber size and the 4–20-fold increase in the number of slow fibers that characterize this condition.

IGF-1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1

It is shown that the molecular pathways underlying the hypertrophic action of IGF-1 in skeletal muscle are similar to those responsible for cardiac hypertrophy.

Stimulation of Slow Skeletal Muscle Fiber Gene Expression by Calcineurin in Vivo *

It is demonstrated that calcineurin activation is sufficient to induce the slow fiber gene regulatory program in vivo and suggest that additional signals are required for skeletal muscle hypertrophy.

Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle

A model of persistent, functional myocyte hypertrophy is generated using a tissue-restricted transgene encoding a locally acting isoform of insulin-like growth factor-1 that is expressed in skeletal muscle (mIgf-1) and suggests clinical strategies for the treatment of age or disease-related muscle frailty.

Matching of Calcineurin Activity to Upstream Effectors Is Critical for Skeletal Muscle Fiber Growth

Findings provide evidence that both calcineurin and its activity-linked upstream signaling elements are crucial for muscle adaptations to OV and that, unless significantly compromised, endogenous levels of this enzyme can accommodate large fluctuations in upstream calcium-dependent signaling events.

Satellite cell activity is required for hypertrophy of overloaded adult rat muscle

The results indicate that satellite cell activation, division, and fusion is necessary for compensatory hypertrophy of fully mature muscle, and may be important to the understanding of the limits of recovery of inherited muscle myopathies treated by myogenic cell implantation.

Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt.

The stage-specific inhibitory action of Akt correlated with its stage- specific ability to form a complex with Raf, suggesting the existence of differentially expressed mediators of an inhibitory Akt-Raf complex.