Date Published: October 24, 2004
Publisher: Public Library of Science
Author(s): Yong-Xu Wang, Chun-Li Zhang, Ruth T Yu, Helen K Cho, Michael C Nelson, Corinne R Bayuga-Ocampo, Jungyeob Ham, Heonjoong Kang, Ronald M Evans
Abstract: Endurance exercise training can promote an adaptive muscle fiber transformation and an increase of mitochondrial biogenesis by triggering scripted changes in gene expression. However, no transcription factor has yet been identified that can direct this process. We describe the engineering of a mouse capable of continuous running of up to twice the distance of a wild-type littermate. This was achieved by targeted expression of an activated form of peroxisome proliferator-activated receptor δ (PPARδ) in skeletal muscle, which induces a switch to form increased numbers of type I muscle fibers. Treatment of wild-type mice with PPARδ agonist elicits a similar type I fiber gene expression profile in muscle. Moreover, these genetically generated fibers confer resistance to obesity with improved metabolic profiles, even in the absence of exercise. These results demonstrate that complex physiologic properties such as fatigue, endurance, and running capacity can be molecularly analyzed and manipulated.
Partial Text: Skeletal muscle fibers are generally classified as type I (oxidative/slow) or type II (glycolytic/fast) fibers. They display marked differences in respect to contraction, metabolism, and susceptibility to fatigue. Type I fibers are mitochondria-rich and mainly use oxidative metabolism for energy production, which provides a stable and long-lasting supply of ATP, and thus are fatigue-resistant. Type II fibers comprise three subtypes, IIa, IIx, and IIb. Type IIb fibers have the lowest levels of mitochondrial content and oxidative enzymes, rely on glycolytic metabolism as a major energy source, and are susceptible to fatigue, while the oxidative and contraction functions of type IIa and IIx lie between type I and IIb (Booth and Thomason 1991; Berchtold et al. 2000; Olson and Williams 2000). Adult skeletal muscle shows plasticity and can undergo conversion between different fiber types in response to exercise training or modulation of motoneuron activity (Booth and Thomason 1991, Jarvis et al. 1996; Pette 1998; Olson and Williams 2000; Hood 2001). This conversion of muscle fiber from type IIb to type IIa and type I is likely to be mediated by a calcium signaling pathway that involves calcineurin, calmodulin-dependent kinase, and the transcriptional cofactor Peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) (Naya et al. 2000; Olson and Williams 2000; Lin et al. 2002; Wu et al. 2002). However, the targeted transcriptional factors directly responsible for reprogramming the fiber-specific contractile and metabolic genes remain to be identified.
Our data reveal that a PPARδ-mediated transcriptional pathway can regulate muscle fiber specification, enabling the generation of a strain of mice with a “long-distance running” phenotype. We show that targeted expression of an activated form of PPARδ produces profound and coordinated increases in oxidation enzymes, mitochondrial biogenesis, and production of specialized type I fiber contractile proteins—the three hallmarks for muscle fiber type switching (Figure 6C). While induction of muscle oxidation enzymes by PPARδ has been seen both in vivo and in vitro (Muoio et al. 2002; Dressel et al. 2003; Luquet et al. 2003; Tanaka et al. 2003; Wang et al. 2003), its effects shown here on muscle fiber switching are unexpected. These progressive changes in oxidative capacity in conjunction with eventual changes in type I muscle fiber lead to a dramatically improved exercise profile and protection against obesity. This does not solely depend on achieving a directed muscle fiber type switch but also requires all the associated changes in neural innervation, motor neuron function, and peripheral metabolic adaptation to enable a new integrated physiological response. Accordingly, activation of muscle PPARδ essentially recapitulates the effects of exercise training even in the absence of training itself. To our knowledge, this has not been directly described for any other transcriptional factor.