G i2 Signaling Promotes Skeletal Muscle Hypertrophy, Myoblast Differentiation, and Muscle Regeneration

Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
Science Signaling (Impact Factor: 6.28). 11/2011; 4(201):ra80. DOI: 10.1126/scisignal.2002038
Source: PubMed


Skeletal muscle atrophy results in loss of strength and an increased risk of mortality. We found that lysophosphatidic acid, which activates a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, stimulated skeletal muscle hypertrophy through activation of Gα(i2). Expression of a constitutively active mutant of Gα(i2) stimulated myotube growth and differentiation, effects that required the transcription factor NFAT (nuclear factor of activated T cells) and protein kinase C. In addition, expression of the constitutively active Gα(i2) mutant inhibited atrophy caused by the cachectic cytokine TNFα (tumor necrosis factor-α) by blocking an increase in the abundance of the mRNA encoding the E3 ubiquitin ligase MuRF1 (muscle ring finger 1). Gα(i2) activation also enhanced muscle regeneration and caused a switch to oxidative fibers. Our study thus identifies a pathway that promotes skeletal muscle hypertrophy and differentiation and demonstrates that Gα(i2)-induced signaling can act as a counterbalance to MuRF1-mediated atrophy, indicating that receptors that act through Gα(i2) might represent potential targets for preventing skeletal muscle wasting.

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Available from: Mara Fornaro, Jun 08, 2015
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    • "In addition, recent work has revealed that both beta adrenergic signaling (Minetti et al., 2011) and bone morphogenetic protein (BMP) signaling (Sartori et al., 2013) can regulate muscle mass and promote skeletal muscle hypertrophy. What is less understood is the role of protein degradation in the remodeling process that occurs in response to loading and leads to an increase in fiber cross-sectional area. "
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    ABSTRACT: The regulation of skeletal muscle mass depends on the balance between protein synthesis and degradation. The role of protein degradation and in particular, the ubiquitin proteasome system, and increased expression of the E3 ubiquitin ligases, MuRF1 and MAFbx/atrogin-1, in the regulation of muscle size in response to growth stimuli is unclear. Thus, the aim of this study was to measure both proteasome activity and protein synthesis in mice over a 14-day period of chronic loading using the functional overload (FO) model. Further, the importance of MuRF1 and MAFbx expression in regulating muscle hypertrophy was examined by measuring muscle growth in response to FO in mice with a null deletion (KO) of either MuRF1 or MAFbx. In wild type (WT) mice, the increase in muscle mass correlated with significant increases (2-fold) in protein synthesis at 7 and 14 days. Interestingly, proteasome activity significantly increased in WT mice after one day, and continued to increase, peaking at 7 days following FO. The increase in proteasome activity was correlated with increases in the expression of the Forkhead transcription factors, FOXO1 and FOXO3a, which increased after both MuRF1 and MAFbx increased and returned to baseline. As in WT mice, hypertrophy in the MuRF1 and MAFbx KO mice was associated with significant increases in proteasome activity after 14 days of FO. The increase in plantaris mass was similar between the WT and MuRF1 KO mice following FO, however, muscle growth was significantly reduced in female MAFbx KO mice. Collectively, these results indicate that muscle hypertrophy is associated with increases in both protein synthesis and degradation. Further, MuRF1 or MAFbx expression is not required to increase proteasome activity following increased loading, however, MAFbx expression may be required for proper growth/remodeling of muscle in response to increase loading.
    Frontiers in Physiology 02/2014; 5:69. DOI:10.3389/fphys.2014.00069 · 3.53 Impact Factor
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    • "More recently, Minetti et al . (2011) demonstrated that a G protein, specifically Gαi2, was essential for the induction of muscle hypertrophy mediated by LPA receptor signaling "
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    ABSTRACT: Abstract The molecular mechanisms underlying skeletal muscle maintenance involve interplay between multiple signaling pathways. Under normal physiological conditions, a network of interconnected signals serves to control and coordinate hypertrophic and atrophic messages, culminating in a delicate balance between muscle protein synthesis and proteolysis. Loss of skeletal muscle mass, termed "atrophy", is a diagnostic feature of cachexia seen in settings of cancer, heart disease, chronic obstructive pulmonary disease, kidney disease, and burns. Cachexia increases the likelihood of death from these already serious diseases. Recent studies have further defined the pathways leading to gain and loss of skeletal muscle as well as the signaling events that induce differentiation and post-injury regeneration, which are also essential for the maintenance of skeletal muscle mass. In this review, we summarize and discuss the relevant recent literature demonstrating these previously undiscovered mediators governing anabolism and catabolism of skeletal muscle.
    Critical Reviews in Biochemistry and Molecular Biology 11/2013; 49(1). DOI:10.3109/10409238.2013.857291 · 7.71 Impact Factor
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    • "In order to compare the molecular profiles of muscle regeneration after glycerol and CTX injection, the Tibialis Anterior muscle of adult wild-type mice was injected with 25 μl of 50% glycerol or 10 µM CTX and compared to a control muscle 3, 7, 14 or 21 days after injection. The dose of glycerol was selected from a pilot study showing that 25 μl of 50% glycerol was able to induce levels of myofiber damage in a slightly lower, yet comparable range than our established model of CTX-induced degeneration (figure S1) [34]. "
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    ABSTRACT: The marbling of skeletal muscle by ectopic adipose tissue is a hallmark of many muscle diseases, including sarcopenia and muscular dystrophies, and generally associates with impaired muscle regeneration. Although the etiology and the molecular mechanisms of ectopic adipogenesis are poorly understood, fatty regeneration can be modeled in mice using glycerol-induced muscle damage. Using comprehensive molecular and histological profiling, we compared glycerol-induced fatty regeneration to the classical cardiotoxin (CTX)-induced regeneration model previously believed to lack an adipogenic response in muscle. Surprisingly, ectopic adipogenesis was detected in both models, but was stronger and more persistent in response to glycerol. Importantly, extensive differential transcriptomic profiling demonstrated that glycerol induces a stronger inflammatory response and promotes adipogenic regulatory networks while reducing fatty acid β-oxidation. Altogether, these results provide a comprehensive mapping of gene expression changes during the time course of two muscle regeneration models, and strongly suggest that adipogenic commitment is a hallmark of muscle regeneration, which can lead to ectopic adipocyte accumulation in response to specific physio-pathological challenges.
    PLoS ONE 08/2013; 8(8):e71084. DOI:10.1371/journal.pone.0071084 · 3.23 Impact Factor
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