Regulation of Muscle Fiber Type and Running Endurance by PPARδ

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.

Variation in the peroxisome proliferator-activated receptor δ gene in relation to common metabolic traits in 7,495 middle-aged white people

“…In recent years PPARδ has emerged as a key protein in the regulation of energy metabolism by its ability to enhance fatty acid catabolism, energy uncoupling and insulin sensitivity in the liver, adipose tissue and skeletal muscle [6][7][8][9][10]36].…”

“…PPARδ acts as a regulator of fatty acid β-oxidation in both adipose tissue and skeletal muscle. In skeletal muscle, overexpression of Ppard in mice increases oxidative metabolism, changes muscle fibre type towards oxidative type I fibres and improves physical endurance thereby averting obesity induced by a high-fat diet or genetically [6,7]. Additionally, a recent study of genetically modified mice provides evidence that PPARδ regulates glucose metabolism and insulin sensitivity in both skeletal muscle and the liver, interestingly indicating a subtle PPARδ-controlled change in substrate utilisation [8].…”

Activation of PPAR-δ in isolated rat skeletal muscle switches fuel preference from glucose to fatty acids

“…The beneficial effects of PPAR-δ on fuel metabolism are attributed to the increased expression of genes involved in lipid metabolism, uncoupling of oxidative phosphorylation, and mitochondrial biogenesis, which leads to elevated energy expenditure and fat dissipation [4,5,8,9]. In this context, the quantitatively most important target organ seems to be skeletal muscle, which makes a major contribution to whole-body fuel oxidation and expresses PPAR-δ more abundantly than other PPAR subtypes [10].…”

“…In this context, the quantitatively most important target organ seems to be skeletal muscle, which makes a major contribution to whole-body fuel oxidation and expresses PPAR-δ more abundantly than other PPAR subtypes [10]. Accordingly, targeted overexpression of PPAR-δ in mouse skeletal muscle distinctly elevates the number of red type-1-like fibres, characterised by high mitochondrial density and oxidative capacity [9,11]. Furthermore, several studies have consistently shown that agonists of PPAR-δ markedly increase the rate of fatty acid oxidation by specimens of skeletal muscle both ex vivo and in vitro [4,5,10].…”

PPARβ/δ Activation Induces Enteroendocrine L Cell GLP-1 Production

“…PPARβ/δ agonist treatment of diabetic db/db, ob/ob or high fat-fed mice reduces weight gain, increases skeletal muscle fatty acid oxidation and decreases plasma triglycerides 31,51,52 . In line with these previous data, our results show that GW501516-treated ob/ob mice also displayed a 10% decrease of body weight in association with a reduction of epididymal adipocyte tissue mass (2.7±0.1 vs. i n s u p e r n a t a n t P P A R β / δ a g o n i s t t r e a t m e n t RNA quantification by real-time PCR.…”