Regulation of Muscle Fiber Type and Running Endurance by PPARδ

By Yong-Xu Wang, Chun-li Zhang, R. Yu, Helen Cho, M. C. Nelson, Corinne R Bayuga-Ocampo, J. Ham, Heonjoong Kang, R. Evans. PLoS Biology, 2004

1,156 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/5e71d452263618a23fbbf48603bd95f11bc3a63c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Johan Auwerx
2. A. Chawla
3. J. Hawley
4. Markku Laakso
5. M. Hock
6. P. Murray
7. Carlo Reggiani
8. S. Schiaffino

In Physiology

1. Johan Auwerx
2. M. Hock
3. A. Kralli
4. A. Chawla
5. J. Hawley
6. C. Choi
7. Shin-Hae Lee
8. Carlo Reggiani

Citations in the corpus

• AMPK and PPARd Agonists Are Exercise Mimetics (2008, neutral): “Pdk4 in quadriceps isolated from vehicle (V)-and GW1516 (GW)-treated wild-type mice, as well as from muscle VP16-PPARd transgenic (Wang et al., 2004) (TG) and nontransgenic (WT) littermates.”
• Transcriptional control of mitochondrial biogenesis and function. (2009, background): “Importantly, these regulatory actions of PPARs are integrated with those of other regulators of mitochondrial biogenesis and function, such as NRF-1 and GABP, via PGC-1α and PGC-1β, which interact physically with PPARs and enhance their ability to induce target genes (7, 45, 46).”
• Fiber types in mammalian skeletal muscles. (2011, background): “These effects appear to be a direct effect of PPAR / activation, as levels of PGC-1 remain unchanged (850).”
• Regulation of energy metabolism by long-chain fatty acids. (2014, background): “PPARd protein is also more abundant in the muscle with oxidative type I fibers than with glycolytic type II fibers [132].”
• The Molecular Bases of Training Adaptation (2007, background): “endurance training is an enhanced capacity for fat utilisation during prolonged exercise, and may also be related to fast-to-slow fibre type conversion (Luquet et al. 2003; Wang et al. 2004).”
• Integrative biology of exercise. (2014, neutral): “…limited to, calcium signaling pathways involving calcineurin, calcium-calmodulin-dependent kinase, and the transcriptional cofactors peroxisome proliferator-activated receptor g coactivator 1 a (PGC-1 a ) and PPAR d (Olson and Williams 2000; Lin et al., 2002; Wang et al., 2004; Wu et al., 2002).”
• Insulin Resistance: From Mechanisms to Therapeutic Strategies (2021, background): “Also, skeletal muscle-specific overexpression of PPARδ improved glucose tolerance and increased number of slow-twitch muscle fibers (a mitochondria rich fiber type) in which mitochondrial oxidative metabolism contributes to energy production [175].”
• Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. (2006, background): “Comparable changes in muscle fiber types have been recapitulated in genetically engineered mouse models that trigger calcium regulatory pathways (Wu et al., 2002), mimic PPARb/d activation (Wang et al., 2004), or enhance PGC-1a activity (Lin et al., 2002a).”
• Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. (2006, background): “In a manner analogous to muscle fiber conversion by metabolic regulators (Lin et al., 2002;Wang et al., 2004), our results suggest a model in which metabolic pathways and their transcriptional regulators serve as key nodal points for directing pro- and antiinflammatory programs of macrophage…”