Increased Insulin Sensitivity and Distorted Mitochondrial Adaptations during Muscle Unloading

Zhengtang Qi,Liu Ji,Shuzhe Ding,Yuan Zhang,Wei Guo

doi:10.3390/ijms131216971

Abstract

We aimed to further investigate mitochondrial adaptations to muscle disuse and the consequent metabolic disorders. Male rats were submitted to hindlimb unloading (HU) for three weeks. Interestingly, HU increased insulin sensitivity index (ISI) and decreased blood level of triglyceride and insulin. In skeletal muscle, HU decreased expression of pyruvate dehydrogenase kinase 4 (PDK4) and its protein level in mitochondria. HU decreased mtDNA content and mitochondrial biogenesis biomarkers. Dynamin-related protein (Drp1) in mitochondria and Mfn2 mRNA level were decreased significantly by HU. Our findings provide more extensive insight into mitochondrial adaptations to muscle disuse, involving the shift of fuel utilization towards glucose, the decreased mitochondrial biogenesis and the distorted mitochondrial dynamics.

Highlights

Hindlimb unloading (HU) is frequently used to simulate and study neuromuscular perturbations occurring in disuse-induced muscle wasting and atrophy [1,2,3,4]
This study aimed to investigate the mitochondrial consequence and the expression of nuclear-encoded genes involved in mitochondrial biogenesis, mitochondrial dynamics and fuel utilization in the unloaded skeletal muscle
The authors emphasized that the enhanced glucose utilization and improved muscle insulin sensitivity during hindlimb suspension were not related to muscle atrophy, because muscle atrophy was not observed in the early stage of muscle unweighting [29]

Summary

Introduction

Hindlimb unloading (HU) is frequently used to simulate and study neuromuscular perturbations occurring in disuse-induced muscle wasting and atrophy [1,2,3,4]. Unloading-induced muscle demonstrates an increased utilization on glucose and a corresponding decreased use of lipid [9] This conversion of fuel source is associated with muscle fiber type switching and further results in activation of glycolysis and inhibition of fatty acid oxidation in unloaded skeletal muscle [10]. An important study suggests that PGC-1 coactivators (α and β) are necessary for the oxidative and mitochondrial programs of skeletal muscle, but are dispensable for fundamental fiber type determination and insulin sensitivity [14]. PGC-1α plays a functional role in exercise-induced mitochondrial biogenesis and angiogenesis, but not IIb-to-IIa fiber-type transformation in skeletal muscle, and the improvement of mitochondrial morphology and antioxidant defense in response to endurance exercise may occur independently of PGC-1α function [16]. In the adaptation to chronic exercise, PGC-1α reduces maximal force, increases resistance to fatigue and drives fiber type switching. partly through remodeling of calcium transients, in addition to promoting slow-type myofibrillar protein expression and adequate energy supply [17]

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