Cold acclimation causes fiber type-specific responses in glucose and fat metabolism in rat skeletal muscles

Diane M Sepa-Kishi,Ayesha Iqbal,Rolando B Ceddia,George Bikopoulos,Yass Sotoudeh-Nia

doi:10.1038/s41598-017-15842-3

Abstract

This study investigated fiber type-specific metabolic responses and the molecular mechanisms that regulate glucose and fat metabolism in oxidative and glycolytic muscles upon cold acclimation. Male Wistar rats were exposed to cold (4 °C) for 7 days, and then glycogen synthesis and content, glucose and palmitate oxidation, and the molecular mechanisms underlying these metabolic pathways were assessed in soleus (Sol), extensor digitorum longus (EDL), and epitrochlearis (Epit) muscles. Cold acclimation increased glycogen synthesis, glycogen content, glucose oxidation, and reduced glycogen synthase (GS) phosphorylation only in Sol muscles. Protein kinase B (AKT), glycogen synthase kinase 3 (GSK3), and AMP-activated protein kinase (AMPK) phosphorylation increased in all three muscles upon cold acclimation. Cold acclimation increased palmitate oxidation, gene expression of the transcriptional co-activator Pgc-1α, lipoprotein lipase (Lpl), fatty acid transporter (Cd36), and Sarco/endoplasmic reticulum Ca2+-ATPase (Serca) in Sol, EDL, and Epit muscles. Sarcolipin was only detected and had its content increased in Sol muscles. In conclusion, cold-induced thermogenesis activated similar signaling pathways in oxidative and glycolytic muscles, but the metabolic fate of glucose differed in skeletal muscles with distinct fiber type composition. Furthermore, only muscles rich in type I fibers appeared to have the capacity for sarcolipin-mediated SERCA uncoupling.

Highlights

Acute cold exposure and cold acclimation in rodents have been reported to markedly increase whole-body energy expenditure[1], which is accompanied by profound metabolic changes including hyperphagia, reduced insulinemia, enhanced hepatic glucose production, and increased glucose and fat utilization by peripheral tissues[1,2,3,4,5,6]
The results of this study provide novel evidence that substrate partitioning is distinctly regulated in oxidative and glycolytic muscles under conditions of cold acclimation
Despite enhancing their ability to utilize glucose to fuel its energy metabolism, Sol muscles increased by ~80% their ability to synthesize glycogen in response to insulin, which was accompanied by 50% and 30% increases in glycogen content under basal and insulin-stimulated conditions, respectively

Summary

Introduction

Acute cold exposure and cold acclimation in rodents have been reported to markedly increase whole-body energy expenditure[1], which is accompanied by profound metabolic changes including hyperphagia, reduced insulinemia, enhanced hepatic glucose production, and increased glucose and fat utilization by peripheral tissues[1,2,3,4,5,6]. Despite the cessation of shivering, glucose and fat metabolism remain elevated in skeletal muscles of cold acclimated rats[1,4], suggesting that mechanisms independent of contractile activity operate to maintain elevated rates of substrate utilization in skeletal muscles in these animals In this context, it has been hypothesized that prolonged cold exposure increases glucose uptake and its metabolism in skeletal muscles by: (a) increasing tissue sensitivity to insulin, and (b) stimulating glucose uptake via insulin-independent pathways[4,14]. The different SERCA isoforms and SLN do not seem to be expressed in oxidative and glycolytic muscles[10,23,24], which suggests that heterogeneity exists with respect to the contribution of SLN-mediated SERCA uncoupling to cold-induced enhancement of glucose and fat metabolism among muscles of different fiber type composition Another potential mechanism by which skeletal muscles could enhance substrate utilization in an insulin-independent manner is through the activation of the cellular energy sensor AMP-activated protein kinase (AMPK). We investigated the insulin-dependent and independent signaling pathways that drive substrate partitioning and assessed the molecular mechanisms underlying the adaptive metabolic responses of oxidative and glycolytic muscles to cold acclimation

Methods

Results

Conclusion