p38gamma mitogen-activated protein kinase is a key regulator in skeletal muscle metabolic adaptation in mice.
Regular endurance exercise induces skeletal muscle contractile and metabolic adaptations, conferring salutary health benefits, such as protection against the metabolic syndrome. The plasticity of skeletal muscle has been extensively investigated, but how the adaptive processes are precisely controlled is largely unknown. Using muscle-specific gene deletion in mice, we now show that p38gamma mitogen-activated protein kinase (MAPK), but not p38alpha and p38beta, is required for endurance exercise-induced mitochondrial biogenesis and angiogenesis, whereas none of the p38 isoforms are required for IIb-to-IIa fiber-type transformation. These phenotypic findings were further supported by microarray and real-time PCR analyses revealing contractile activity-dependent p38gamma target genes, including peroxisome proliferator-activated receptor gamma co-activator-1alpha (Pgc-1alpha) and vascular endothelial growth factor (Vegf), in skeletal muscle following motor nerve stimulation. Gene transfer-mediated overexpression of a dominant negative form of p38gamma, but not that of p38alpha or p38beta, blocked motor nerve stimulation-induced Pgc-1alpha transcription. These findings provide direct evidence for an obligated role of p38gamma MAPK-PGC-1alpha regulatory axis in endurance exercise-induced metabolic adaptation, but not contractile adaptation, in skeletal muscle.
Pogozelski
Andrew R
AR
Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
Geng
Tuoyu
T
Li
Ping
P
Yin
Xinhe
X
Lira
Vitor A
VA
Zhang
Mei
M
Chi
Jen-Tsan
JT
Yan
Zhen
Z
D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D005799:Genes, Dominant; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D020033:Protein Isoforms; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000502:physiology*
D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D020033:Protein Isoforms; D015534:Trans-Activators; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases