Swim Training Modulates Mouse Skeletal Muscle Energy Metabolism and Ameliorates Reduction in Grip Strength in a Mouse Model of Amyotrophic Lateral Sclerosis.

Damian Jozef Flis,Katarzyna Dzik,Mariusz Roman Wieckowski,Jedrzej Antosiewicz,Wieslaw Ziolkowski,Malgorzata Halon-Golabek,Karol Cieminski,Jan Jacek Kaczor

doi:10.3390/ijms20020233

Abstract

Metabolic reprogramming in skeletal muscles in the human and animal models of amyotrophic lateral sclerosis (ALS) may be an important factor in the diseases progression. We hypothesized that swim training, a modulator of cellular metabolism via changes in muscle bioenergetics and oxidative stress, ameliorates the reduction in muscle strength in ALS mice. In this study, we used transgenic male mice with the G93A human SOD1 mutation B6SJL-Tg (SOD1G93A) 1Gur/J and wild type B6SJL (WT) mice. Mice were subjected to a grip strength test and isolated skeletal muscle mitochondria were used to perform high-resolution respirometry. Moreover, the activities of enzymes involved in the oxidative energy metabolism and total sulfhydryl groups (as an oxidative stress marker) were evaluated in skeletal muscle. ALS reduces muscle strength (−70% between 11 and 15 weeks, p < 0.05), modulates muscle metabolism through lowering citrate synthase (CS) (−30% vs. WT, p = 0.0007) and increasing cytochrome c oxidase and malate dehydrogenase activities, and elevates oxidative stress markers in skeletal muscle. Swim training slows the reduction in muscle strength (−5% between 11 and 15 weeks) and increases CS activity (+26% vs. ALS I, p = 0.0048). Our findings indicate that swim training is a modulator of skeletal muscle energy metabolism with concomitant improvement of skeletal muscle function in ALS mice.

Highlights

Amyotrophic lateral sclerosis (ALS) is an incurable, chronic neurodegenerative disease characterized by selective death of motoneurons in the motor cortex, brainstem, and spinal cord, which controls muscle action [1]
The discovery of the role of mutations in the superoxide dismutase type 1 (SOD1) gene in the etiology of ALS has contributed to constructing the most suitable animal test model of the disease, containing the human SOD1 G93A transgene described by Gurney [5], where glycine is changed to alanine at position 93
ReTshueltsprogression of ALS leads to muscle weakness and atrophy, which are associated with deterTiohreatpiornoginremssuiosncleosftrAenLgSthle.aTdhserteofomreu,stcoleaswseesasktnhesesffaenctds oaftrsowpihmy,trwaihniicnhg aornethasesgorciipatsetdrenwgith odfetAerLioSramtiocne,inwme ususcbljeecsteredngbtoht.hTwheilrdef-otyrpe,eto(WasTse)sasntdheheSfOfeDcts1 oGf9s3wAimmtorauisneinggrounpths etograiprsetgriemngetnh of eAxLeSrcmisiec.eO, wverstuibmjeec,tuedntbroaitnhewdilmd-ictyepleos(Wt gTr)ipansdtrehnSgOtDh 1asG9a3rAesmulotuosfetghreoupprosgtoreassrieognimofenthoef dexiseeracissee

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is an incurable, chronic neurodegenerative disease characterized by selective death of motoneurons in the motor cortex, brainstem, and spinal cord, which controls muscle action [1]. This disease is phenotypically characterized by loss of muscle tone, paresis, muscle atrophy, and spasticity [2]. 90% of ALS is a sporadic form of disease (sALS), for which the etiology is unknown, and the remaining percentage is a genetically determined form (fALS). In clinical terms, both forms are virtually identical. Additional support for the view that muscle plays a key role in ALS pathogenesis has been provided by the observations that the destruction of neuromuscular junctions is linked to oxidative stress induced by tissue-specific breakdown of muscle mitochondria [8]

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