Atrogin-1/MAFbx and MuRF1 are downregulated in aging-related loss of skeletal muscle.
Muscle atrophy in many conditions share a common mechanism in the upregulation of the muscle-specific ubiquitin E3-ligases atrophy gene-1/muscle atrophy F-box (Atrogin-1/MAFbx) and muscle ring-finger protein 1 (MuRF1). E3-ligases are part of the ubiquitin proteasome pathway utilized for protein degradation during muscle atrophy. In this study, we provide new data to show that this is not the case in age-related loss of muscle mass (sarcopenia). On the contrary, Atrogin-1/MAFbx and MuRF1 are downregulated in skeletal muscle of 30-month-old rats, and our results suggest that AKT (protein kinase B)-mediated inactivation of forkhead box O 4 (FOXO4) underlies this suppression. The data also suggest that activation of AKT is mediated through the insulin-like growth factor-1 (IGF-1) receptor, signaling via ShcA-Grb2-GAB. Using dietary restriction, we find that it impedes sarcopenia as well as the effects of aging on AKT phosphorylation, FOXO4 phosphorylation, and Atrogin-1/MAFbx and MuRF1 transcript regulation. We conclude that sarcopenia is mechanistically different from acute atrophies induced by disuse, disease, and denervation.
Edström
Erik
E
Department of Neuroscience, Karolinska Institutet, Neuroscience, A3:4, Stockholm, Sweden 17177. erik.edstrom@ki.se
Altun
Mikael
M
Hägglund
Martin
M
Ulfhake
Brun
B
D000375:Aging / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D015536:Down-Regulation; D005260:Female; D009124:Muscle Proteins / Q000096:biosynthesis*; D018482:Muscle, Skeletal / Q000201:enzymology*; D009133:Muscular Atrophy / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000096:biosynthesis*; D015398:Signal Transduction; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis*
D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases