Opposed growth factor signals control protein degradation in muscles of Caenorhabditis elegans.
In addition to contractile function, muscle provides a metabolic buffer by degrading protein in times of organismal need. Protein is also degraded during adaptive muscle remodeling upon exercise, but extreme degradation in diverse clinical conditions can compromise function(s) and threaten life. Here, we show how two independent signals interact to control protein degradation. In striated muscles of Caenorhabditis elegans, reduction of insulin-like signaling via DAF-2 insulin/IGF receptor or its intramuscular effector PtdIns-3-kinase (PI3K) causes unexpected activation of MAP kinase (MAPK), consequent activation of pre-existing systems for protein degradation, and progressive impairment of mobility. Degradation is prevented by mutations that increase signal downstream of PI3K or by disruption of autocrine signal from fibroblast growth factor (FGF) via the FGF receptor and its effectors in the Ras-MAPK pathway. Thus, the activity of constitutive protein degradation systems in normal muscle is minimized by a balance between directly interacting signaling pathways, implying that physiological, pathological, or therapeutic alteration of this balance may contribute to muscle remodeling or wasting.
Szewczyk
Nathaniel J
NJ
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Peterson
Brant K
BK
Barmada
Sami J
SJ
Parkinson
Leah P
LP
Jacobson
Lewis A
LA
D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D004586:Electrophoresis; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005470:Fluorometry; D005819:Genetic Markers / Q000235:genetics; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D009133:Muscular Atrophy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; D005819:Genetic Markers; D007328:Insulin; D009124:Muscle Proteins; D005346:Fibroblast Growth Factors; D019869:Phosphatidylinositol 3-Kinases; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin; D020928:Mitogen-Activated Protein Kinases