Oxidative status of muscle is determined by p107 regulation of PGC-1alpha.
Mice lacking p107 exhibit a white adipose deficiency yet do not manifest the metabolic changes typical for lipodystrophy, and instead exhibit low levels of serum triglycerides and a normal liver phenotype. When fed a high fat diet, p107-null mice still did not accumulate fat in the liver, and display markedly elevated energy expenditures together with an increased energy preference for lipids. Skeletal muscle was therefore examined, as this is normally the major tissue involved in whole body lipid metabolism. Notably, p107-deficient muscle express increased levels of peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha) and contained increased numbers of the pro-oxidative type I and type IIa myofibers. Chromatin immunoprecipitation revealed binding of p107 and E2F4 to the PGC-1alpha proximal promoter, and this binding repressed promoter activity in transient transcription assays. Ectopic expression of p107 in muscle tissue in vivo results in a pronounced 20% decrease in the numbers of oxidative type IIa myofibers. Lastly, isolated p107-deficient muscle tissue display a threefold increase in lipid metabolism. Therefore, p107 determines the oxidative state of multiple tissues involved in whole body fat metabolism, including skeletal muscle.
Scimè
Anthony
A
Regenerative Medicine Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada.
Soleimani
Vahab D
VD
Bentzinger
C Florian
CF
Gillespie
Mark A
MA
Le Grand
Fabien
F
Grenier
Guillaume
G
Bevilacqua
Lisa
L
Harper
Mary-Ellen
ME
Rudnicki
Michael A
MA
D052436:Adipose Tissue, White / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D002151:Calorimetry; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism; D005260:Female; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic
D004041:Dietary Fats; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C489485:Rbl1 protein, mouse; D050720:Retinoblastoma-Like Protein p107; D015534:Trans-Activators; D014157:Transcription Factors