Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres.
The biochemical basis for the regulation of fibre-type determination in skeletal muscle is not well understood. In addition to the expression of particular myofibrillar proteins, type I (slow-twitch) fibres are much higher in mitochondrial content and are more dependent on oxidative metabolism than type II (fast-twitch) fibres. We have previously identified a transcriptional co-activator, peroxisome-proliferator-activated receptor-gamma co-activator-1 (PGC-1 alpha), which is expressed in several tissues including brown fat and skeletal muscle, and that activates mitochondrial biogenesis and oxidative metabolism. We show here that PGC-1 alpha is expressed preferentially in muscle enriched in type I fibres. When PGC-1 alpha is expressed at physiological levels in transgenic mice driven by a muscle creatine kinase (MCK) promoter, a fibre type conversion is observed: muscles normally rich in type II fibres are redder and activate genes of mitochondrial oxidative metabolism. Notably, putative type II muscles from PGC-1 alpha transgenic mice also express proteins characteristic of type I fibres, such as troponin I (slow) and myoglobin, and show a much greater resistance to electrically stimulated fatigue. Using fibre-type-specific promoters, we show in cultured muscle cells that PGC-1 alpha activates transcription in cooperation with Mef2 proteins and serves as a target for calcineurin signalling, which has been implicated in slow fibre gene expression. These data indicate that PGC-1 alpha is a principal factor regulating muscle fibre type determination.
Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Jiandie
J
Lin
Hai
H
Wu
Paul T
PT
Tarr
Chen-Yu
CY
Zhang
Zhidan
Z
Wu
Olivier
O
Boss
Laura F
LF
Michael
Pere
P
Puigserver
Eiji
E
Isotani
Eric N
EN
Olson
Bradford B
BB
Lowell
Rhonda
R
Bassel-Duby
Bruce M
BM
Spiegelman
D000818:Animals; D002460:Cell Line; D003402:Creatine Kinase / Q000235:genetics; D052283:Creatine Kinase, MM Form; D004268:DNA-Binding Proteins / Q000378:metabolism; D004558:Electric Stimulation; D007527:Isoenzymes / Q000235:genetics; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D018763:Muscle Fatigue; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism*; D018006:Myogenic Regulatory Factors; D009211:Myoglobin / Q000032:analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D019076:Transgenes / Q000235:genetics; D019210:Troponin I / Q000032:analysis
D004268:DNA-Binding Proteins; D007527:Isoenzymes; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D009211:Myoglobin; D014157:Transcription Factors; D019210:Troponin I; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D003402:Creatine Kinase; D052283:Creatine Kinase, MM Form