G alpha(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: 7.65). 11/2011; 4(201):ra80. DOI: 10.1126/scisignal.2002038
Source: PubMed

ABSTRACT 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.

Download full-text


Available from: Mara Fornaro, Jun 08, 2015
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 3.50 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Activation of G protein-coupled receptors is involved in regulating many cellular responses, but less is known regarding the role of these receptors in the differentiation and maintenance of skeletal muscle. New findings implicate the inhibitor subunit Gα(i2) as a vital mediator of myofiber maturation and growth, operating through multiple signaling pathways to selectively stimulate protein synthesis or inhibit cytokine-dependent protein turnover.
    Science Signaling 11/2011; 4(201):pe45. DOI:10.1126/scisignal.2002670 · 7.65 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Among organ systems, skeletal muscle is perhaps the most structurally specialized. The remarkable subcellular architecture of this tissue allows it to empower movement with instructions from motor neurons. Despite this high degree of specialization, skeletal muscle also has intrinsic signaling mechanisms that allow adaptation to long-term changes in demand and regeneration after acute damage. The second messenger adenosine 3',5'-monophosphate (cAMP) not only elicits acute changes within myofibers during exercise but also contributes to myofiber size and metabolic phenotype in the long term. Strikingly, sustained activation of cAMP signaling leads to pronounced hypertrophic responses in skeletal myofibers through largely elusive molecular mechanisms. These pathways can promote hypertrophy and combat atrophy in animal models of disorders including muscular dystrophy, age-related atrophy, denervation injury, disuse atrophy, cancer cachexia, and sepsis. cAMP also participates in muscle development and regeneration mediated by muscle precursor cells; thus, downstream signaling pathways may potentially be harnessed to promote muscle regeneration in patients with acute damage or muscular dystrophy. In this review, we summarize studies implicating cAMP signaling in skeletal muscle adaptation. We also highlight ligands that induce cAMP signaling and downstream effectors that are promising pharmacological targets.
    AJP Endocrinology and Metabolism 02/2012; 303(1):E1-17. DOI:10.1152/ajpendo.00555.2011 · 4.09 Impact Factor
Show more