The Transcriptional Coactivator PGC-1β Drives the Formation of Oxidative Type IIX Fibers in Skeletal Muscle

Abstract

Skeletal muscle must perform different kinds of work, and distinct fiber types have evolved to accommodate these. Previous work had shown that the transcriptional coactivator PGC-1alpha drives the formation of type I and IIA muscle fibers, which are "slow-twitch" and highly oxidative. We show here that transgenic expression of PGC-1beta, a coactivator functionally similar to but distinct from PGC-1alpha, causes a marked induction of IIX fibers, which are oxidative but have "fast-twitch" biophysical properties. PGC-1beta coactivates the MEF2 family of transcription factors to stimulate the type IIX myosin heavy chain (MHC) promoter. PGC-1beta transgenic muscle fibers are rich in mitochondria and are highly oxidative, at least in part due to coactivation by PGC-1beta of ERRalpha and PPARalpha. Consequently, these transgenic animals can run for longer and at higher work loads than wild-type animals. Together, these data indicate that PGC-1beta drives the formation of highly oxidative fibers containing type IIX MHC.

Potential therapeutic interventions for chronic kidney disease‐associated sarcopenia via indoxyl sulfate‐induced mitochondrial dysfunction

“…Previous reports and our in vitro experiments ( Figure 1) demonstrated that there is mutual relationship between exercise capacity in treadmill experiments and muscular mitochondrial function 6, 9, 10, 19. We therefore further evaluated the mitochondrial status in skeletal muscle of CKD mice.…”

“…The amount of mitochondria is regulated by both mitochondria biosynthesis and its degradation 9, 10. Tamaki et al recently reported that the amount of muscular mitochondria was decreased in the early stage of CKD mice and that it was associated with increased oxidative stress and inflammatory cytokines, such as tumor necrosis factor (TNF)‐α and interleukin (IL)‐6 6.…”

Nuclear receptors, mitochondria and lipid metabolism

“…Mitochondrial biogenesis and respiration are highly dependent on the transcriptional coactivators, PGC-1α and β, and their interacting factors (Puigserver et al 1998;Wu et al 1999;Lehman et al 2000;Lin et al 2002;Kelly and Scarpulla 2004;Arany et al 2007;Sonoda et al 2007). In addition, many physiologic, hormonal and dietary cues are transduced into adaptive protein changes via the transcriptional coactivator PGC-1α.…”

Are cultured human myotubes far from home?

“…Slow fiber type genes were also shown to be upregulated by the extracellular signal-regulated kinases (ERK) pathway in rats (Murgia, et al, 2000) and by peroxisome-proliferator-activated receptor-gamma co-activator-1 alpha (PGC-1α) in mice (Lin, et al, 2002). PGC-1β, on the other hand, is involved in fast twitch (type 2X) fiber transition (Arany, et al, 2007). In human skeletal muscle in vivo there seems to be a correlation between the expression of the peroxisome proliferator-activated receptors (PPAR) α and δ and proportion of type 1 fibers (Kramer, et al, 2006, Russell, et al, 2003.…”