Postnatal PPARδ Activation and Myostatin Inhibition Exert Distinct yet Complimentary Effects on the Metabolic Profile of Obese Insulin-Resistant Mice

Abstract

BackgroundInterventions for T2DM have in part aimed to mimic exercise. Here, we have compared the independent and combined effects of a PPARδ agonist and endurance training mimetic (GW501516) and a myostatin antibody and resistance training mimetic (PF-879) on metabolic and performance outcomes in obese insulin resistant mice.Methodology/Principal FindingsMale ob/ob mice were treated for 6 weeks with vehicle, GW501516, PF-879, or GW501516 in combination with PF-879. The effects of the interventions on body composition, glucose homeostasis, glucose tolerance, energy expenditure, exercise capacity and metabolic gene expression were compared at the end of study. GW501516 attenuated body weight and fat mass accumulation and increased the expression of genes of oxidative metabolism. In contrast, PF-879 increased body weight by driving muscle growth and altered the expression of genes involved in insulin signaling and glucose metabolism. Despite their differences, both interventions alone improved glucose homeostasis. Moreover, GW501516 more effectively improved serum lipids, and PF-879 uniquely increased energy expenditure, exercise capacity and adiponectin levels. When combined the robust effects of GW501516 and/or PF-879 on body weight, adiposity, muscle mass, glycemia, serum lipids, energy expenditure and exercise capacity were highly conserved.Conclusions/SignificanceThe data, for the first time, demonstrate postnatal inhibition of myostatin not only promotes gains in muscle mass similar to resistance training,but improves metabolic homeostasis. In several instances, these effects were either distinct from or complimentary to those of GW501516. The data further suggest that strategies to increase muscle mass, and not necessarily oxidative capacity, may effectively counter insulin resistance and T2DM.

Peroxisome Proliferator-activated Receptor β/δ Induces Myogenesis by Modulating Myostatin Activity

“…Specifically, activation of PPAR␤/␦ results in increased utrophin A transcript levels in mdx mice (a model of Duchene muscular dystrophy), which is a protein that can functionally compensate for the loss of dystrophin in mdx mice and as such helps to maintain the sarcolemmal integrity of degenerating muscle fibers. A very recent study reports that postnatal activation of PPAR␤/␦ results in a similar effect on muscle metabolism to that observed following inhibition of myostatin (24), a TGF-␤ superfamily member and potent negative regulator of myogenesis (25,26). Postnatal activation of PPAR␤/␦ by GW501516 and neutralization of myostatin activity via PF-879 antibody in ob/ob mice results in reduced fat mass, improved glucose tolerance, and reduced muscle triglyceride and free fatty acid levels (24); this study clearly demonstrates that there is some degree of similarity between PPAR␤/␦ activation and myostatin inhibition, at least during postnatal growth.…”

“…A very recent study reports that postnatal activation of PPAR␤/␦ results in a similar effect on muscle metabolism to that observed following inhibition of myostatin (24), a TGF-␤ superfamily member and potent negative regulator of myogenesis (25,26). Postnatal activation of PPAR␤/␦ by GW501516 and neutralization of myostatin activity via PF-879 antibody in ob/ob mice results in reduced fat mass, improved glucose tolerance, and reduced muscle triglyceride and free fatty acid levels (24); this study clearly demonstrates that there is some degree of similarity between PPAR␤/␦ activation and myostatin inhibition, at least during postnatal growth. Given the benefits associated with PPAR␤/␦ activation and skeletal muscle growth, we attempted to delineate the mechanism(s) through which PPAR␤/␦ regulates muscle growth.…”

Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice

“…Indeed, myostatin knockout mice display increased energy expenditure (29) and protection against lipid-induced insulin resistance, glucose intolerance, and HFD-induced obesity (16,(30)(31)(32). In contrast with these studies, LeBrasseur et al (27) did not observe an improvement in glucose tolerance and insulin sensitivity in aged …”

Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway

“…In extremely obese human participants it was further discovered that there were elevated levels of MSTN protein in both muscle and plasma samples [17]. In addition, injection of MSTNspecific antibodies along with exercise results in significantly increased insulin sensitivity [18]. Recently, Guo et al showed that inhibition of MSTN signalling, specifically in adipose tissue, had no effect on glucose and insulin tolerance [12].…”