Skeletal muscles not only provide the contractile forces required for movement but also serve to produce heat and to provide an energy reserve for organismal metabolism. This metabolic "buffering" capacity takes the form of protein catabolism, which occurs in times of adaptive muscle remodeling or organismal starvation or in certain pathological settings. Szewczyk et al. studied the signals that control muscle protein degradation in Caenorhabditis elegans using mutant animals expressing either green fluorescent protein (GFP) in the muscle or GFP myofibrillar fusion proteins. Under conditions in which insulin-like growth factor (IGF) signaling was inhibited, muscle protein degradation was stimulated. Mutations (or pharmacological agents) that inhibited the activity of the IGF receptor or the activity of phosphatidylinositol 3-kinase (PI3K) stimulated muscle protein degradation and decreased animal movement, whereas gain-of-function mutations in Akt or the lipid phosphatase that opposes PI3K function prevented muscle protein degradation triggered by the decreased IGF signaling. Fibroblast growth factor receptor (FGFR) activation of the Ras-MAPK (mitogen-activated protein kinase) pathway is known to stimulate muscle protein degradation in C. elegans. Szewczyk et al. showed that IGF signaling opposes FGF signaling to prevent muscle protein degradation. Mutations in the FGF-Ras-MAPK pathway prevented protein degradation in response to loss of PI3K activity. Inhibition of PI3K also stimulated the formation of the diphosphorylated activated form of MAPK, further supporting an intersection between IGF signaling and the Ras-MAPK pathway. Raf is a putative target for Akt phosphorylation, and animals expressing a mutant form of Raf that was not phosphorylatable by Akt showed increased muscle degradation and the appearance of the activated form of MAPK. The animals appear poised to degrade the muscle proteins in response to FGF signaling, and IGF signaling provides the brake preventing muscle protein degradation.
N. J. Szewczyk, B. K. Peterson, S. J. Barmada, L. P. Parkinson, L. A. Jacobson, Opposed growth factor signals control protein degradation in muscles of Caenorhabditis elegans. EMBO J. 26, 935-943 (2007). [PubMed]