Skeletal muscle fiber-type switching, exercise intolerance, and myopathy in PGC-1alpha muscle-specific knock-out animals.
The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is a key integrator of neuromuscular activity in skeletal muscle. Ectopic expression of PGC-1alpha in muscle results in increased mitochondrial number and function as well as an increase in oxidative, fatigue-resistant muscle fibers. Whole body PGC-1alpha knock-out mice have a very complex phenotype but do not have a marked skeletal muscle phenotype. We thus analyzed skeletal muscle-specific PGC-1alpha knock-out mice to identify a specific role for PGC-1alpha in skeletal muscle function. These mice exhibit a shift from oxidative type I and IIa toward type IIx and IIb muscle fibers. Moreover, skeletal muscle-specific PGC-1alpha knock-out animals have reduced endurance capacity and exhibit fiber damage and elevated markers of inflammation following treadmill running. Our data demonstrate a critical role for PGC-1alpha in maintenance of normal fiber type composition and of muscle fiber integrity following exertion.
Handschin
Christoph
C
Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Chin
Sherry
S
Li
Ping
P
Liu
Fenfen
F
Maratos-Flier
Eleftheria
E
Lebrasseur
Nathan K
NK
Yan
Zhen
Z
Spiegelman
Bruce M
BM
D000818:Animals; D006019:Glycolysis; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D018656:Muscle Fibers, Fast-Twitch / Q000502:physiology*; D018657:Muscle Fibers, Slow-Twitch / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009135:Muscular Diseases / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D010805:Physical Conditioning, Animal; D014157:Transcription Factors / Q000096:biosynthesis*
D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D010100:Oxygen