Molecular signaling pathways regulating muscle proteolysis during atrophy.
OBJECTIVE
Although a variety of diverse stimuli induce muscle atrophy, there is a surprising number of similarities in the intracellular responses. One prominent response is an increase in muscle proteolysis resulting from stimulation of the ubiquitin-proteasome pathway. Understanding the intracellular signaling pathways that regulate muscle mass should offer insights into the coordination of cellular responses. This review will discuss recent findings on the molecular signaling pathways regulating proteolysis during muscle atrophy.


RESULTS
The expression of several muscle-specific E3 ubiquitin ligases is consistently increased in conditions causing muscle atrophy. Insulin and insulin-like growth factor-1 act through the phosphoinositide 3-kinase/AKT pathway to suppress the expression of two of these enzymes, MuRF1 and MAFbx/atrogin-1. Efforts to identify targets of the muscle-specific E3 ligases are yielding interesting information. Insulin and insulin-like growth factor-1 also attenuate wasting by inhibiting caspase-3, which cleaves actin to facilitate its destruction by the ubiqutin-proteasome system. Other signaling systems involved in the regulation of muscle mass include the nuclear factor kappa B pathway.


CONCLUSIONS
The maintenance of muscle mass requires a delicate balance between catabolic factors and anabolic factors. These signals inversely modulate the activity of several key regulatory pathways including the phosphoinositide-3 kinase/AKT and nuclear factor kappa B systems, which control the transcription of components of the ubiquitin-proteasome proteolytic pathway activity, the activity of caspase-3, and perhaps other proteolytic functions. When levels of insulin or insulin-like growth factor-1 are insufficient or inflammatory cytokine production is increased, muscle atrophy ensues.
Franch
Harold A
HA
Renal Division, Emory University, Atlanta, GA 30322, USA.
Price
S Russ
SR
D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D009133:Muscular Atrophy / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology; D010447:Peptide Hydrolases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D009124:Muscle Proteins; D016328:NF-kappa B; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; D044767:Ubiquitin-Protein Ligases; D019869:Phosphatidylinositol 3-Kinases; D010447:Peptide Hydrolases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D046988:Proteasome Endopeptidase Complex