Exercise Preconditioning Blunts Early Atrogenes Expression and Atrophy in Gastrocnemius Muscle of Hindlimb Unloaded Mice.

Lorenza Brocca,Monica Canepari,Maria Antonietta Pellegrino,Maira Rossi,Roberto Bottinelli

doi:10.3390/ijms23010148

Abstract

A large set of FoxOs-dependent genes play a primary role in controlling muscle mass during hindlimb unloading. Mitochondrial dysfunction can modulate such a process. We hypothesized that endurance exercise before disuse can protect against disuse-induced muscle atrophy by enhancing peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) expression and preventing mitochondrial dysfunction and energy-sensing AMP-activated protein kinase (AMPK) activation. We studied cross sectional area (CSA) of muscle fibers of gastrocnemius muscle by histochemistry following 1, 3, 7, and 14 days of hindlimb unloading (HU). We used Western blotting and qRT-PCR to study mitochondrial dynamics and FoxOs-dependent atrogenes’ expression at 1 and 3 days after HU. Preconditioned animals were submitted to moderate treadmill exercise for 7 days before disuse. Exercise preconditioning protected the gastrocnemius from disuse atrophy until 7 days of HU. It blunted alterations in mitochondrial dynamics up to 3 days after HU and the expression of most atrogenes at 1 day after disuse. In preconditioned mice, the activation of atrogenes resumed 3 days after HU when mitochondrial dynamics, assessed by profusion and pro-fission markers (mitofusin 1, MFN1, mitofusin 2, MFN2, optic atrophy 1, OPA1, dynamin related protein 1, DRP1 and fission 1, FIS1), PGC1α levels, and AMPK activation were at a basal level. Therefore, the normalization of mitochondrial dynamics and function was not sufficient to prevent atrogenes activation just a few days after HU. The time course of sirtuin 1 (SIRT1) expression and content paralleled the time course of atrogenes’ expression. In conclusion, seven days of endurance exercise counteracted alterations of mitochondrial dynamics and the activation of atrogenes early into disuse. Despite the normalization of mitochondrial dynamics, the effect on atrogenes’ suppression died away within 3 days of HU. Interestingly, muscle protection lasted until 7 days of HU. A longer or more intense exercise preconditioning may prolong atrogenes suppression and muscle protection.

Highlights

Disuse-induced loss of muscle mass is a frequent phenomenon occurring in a variety of conditions such as immobilization following traumatic lesions, deconditioning, ageing, and in chronic diseases
We recently reported that 96% of genes related to hindlimb unloading (HU)- induced muscle atrophy are under FoxO control and seventeen are the core machinery for protein breakdown [26]
We studied the full set of FoxOdependent atrogenes we previously found to control muscle mass in the gastrocnemius following HU, as Atrogin1 and MuRF1 might not play a major role in the process [26]

Summary

Introduction

Disuse-induced loss of muscle mass is a frequent phenomenon occurring in a variety of conditions such as immobilization following traumatic lesions, deconditioning, ageing, and in chronic diseases. It is related to metabolic alterations, such as insulin resistance, as well as low-grade chronic inflammation [1], which are among the major risk factors of chronic diseases [2]. It worsens the prognosis of many chronic diseases [3], which benefit from exercise training [2,4]. A metabolic program, based on mitochondrial dysfunction and PGC1α down-regulation, is believed to play a major role in skeletal muscle atrophy. The observation that muscle overexpression of PGC1α blunted or prevented HU-induced atrophy in both muscles by counteracting the activation of catabolic pathways strengthened the idea that mitochondrial dysfunction plays a major role in disuse atrophy [8,13]

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