Adaptation of Mouse Skeletal Muscle to Long-Term Microgravity in the MDS Mission

Dorianna Sandonà,Romeo Betto,Elena Germinario,Martina Gutsmann,Fuminori Kawano,Gudrun Schiffl,Michele Salanova,Dieter Blottner,Sandra Furlan,Yoshinobu Ohira,Elisa Bianchini,Stefano Ciciliot,Daniela Danieli-Betto,Gabriella Dobrowolny,Anne Picard,Yoshitaka Ohno,Stefano Schiaffino,Katsumasa Goto,Takashi Ohira,Antonio Musarò ,Claudia Camerino ,Diana Conte Camerino ,Jean-François Desaphy ,Norihiro Nakai

doi:10.1371/journal.pone.0033232

Abstract

The effect of microgravity on skeletal muscles has so far been examined in rat and mice only after short-term (5–20 day) spaceflights. The mice drawer system (MDS) program, sponsored by Italian Space Agency, for the first time aimed to investigate the consequences of long-term (91 days) exposure to microgravity in mice within the International Space Station. Muscle atrophy was present indistinctly in all fiber types of the slow-twitch soleus muscle, but was only slightly greater than that observed after 20 days of spaceflight. Myosin heavy chain analysis indicated a concomitant slow-to-fast transition of soleus. In addition, spaceflight induced translocation of sarcolemmal nitric oxide synthase-1 (NOS1) into the cytosol in soleus but not in the fast-twitch extensor digitorum longus (EDL) muscle. Most of the sarcolemmal ion channel subunits were up-regulated, more in soleus than EDL, whereas Ca2+-activated K+ channels were down-regulated, consistent with the phenotype transition. Gene expression of the atrophy-related ubiquitin-ligases was up-regulated in both spaceflown soleus and EDL muscles, whereas autophagy genes were in the control range. Muscle-specific IGF-1 and interleukin-6 were down-regulated in soleus but up-regulated in EDL. Also, various stress-related genes were up-regulated in spaceflown EDL, not in soleus. Altogether, these results suggest that EDL muscle may resist to microgravity-induced atrophy by activating compensatory and protective pathways. Our study shows the extended sensitivity of antigravity soleus muscle after prolonged exposition to microgravity, suggests possible mechanisms accounting for the resistance of EDL, and individuates some molecular targets for the development of countermeasures.

Highlights

Adult skeletal muscles are well differentiated into slowand fast-twitch fibers, they are still able to adapt their phenotype in response to modified functional requests by expressing specific forms or levels of proteins contributing to excitability, E-C coupling, contraction, calcium handling, and energy metabolism [1]
Transcript levels of Pax-7 remained unchanged after space flight, consistent with the knowledge that skeletal muscle adaptation to inactivity is a physiological response not associated to pathological events
Atrophy was evident in soleus muscle, but was absent in extensor digitorum longus (EDL) muscle

Summary

Introduction

Adult skeletal muscles are well differentiated into slowand fast-twitch fibers, they are still able to adapt their phenotype in response to modified functional requests by expressing specific forms or levels of proteins contributing to excitability, E-C coupling, contraction, calcium handling, and energy metabolism [1]. Muscle mass is critically dependent on chronic functional demand. Reduction of muscle mass (atrophy) and alteration of muscle function during spaceflight cause serious medical problems for astronauts upon return to Earth. Reduced muscle strength and endurance capacity and enhanced muscle fragility may impair postural maintenance and locomotion activity. During a long-duration space mission, the alteration of muscle performance may reduce the ability of astronauts to perform specific tasks. There is a critical need for understanding the molecular mechanisms responsible for muscle impairment to identify possible targets for countermeasures

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