Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice

Graziana Colaianni,Saverio Cinti,Paolo Pignataro,Roberto Vettor,Concetta Cuscito,Ilenia Severi,Angela Notarnicola,Luciana Lippo,Giorgio Mori,Silvia C Colucci,Teresa Mongelli,Maria Grano,Biagio Moretti,Giacomina Brunetti,Umberto Tarantino,Giovanna Spiro,Giovanni Passeri,Janne E Reseland

doi:10.1038/s41598-017-02557-8

Abstract

We previously showed that Irisin, a myokine released from skeletal muscle after physical exercise, plays a central role in the control of bone mass. Here we report that treatment with recombinant Irisin prevented bone loss in hind-limb suspended mice when administered during suspension (preventive protocol) and induced recovery of bone mass when mice were injected after bone loss due to a suspension period of 4 weeks (curative protocol). MicroCT analysis of femurs showed that r-Irisin preserved both cortical and trabecular bone mineral density, and prevented a dramatic decrease of the trabecular bone volume fraction. Moreover, r-Irisin protected against muscle mass decline in the hind-limb suspended mice, and maintained the fiber cross-sectional area. Notably, the decrease of myosin type II expression in unloaded mice was completely prevented by r-Irisin administration. Our data reveal for the first time that Irisin retrieves disuse‐induced bone loss and muscle atrophy. These findings may lead to development of an Irisin-based therapy for elderly immobile osteoporotic and physically disable patients, and might represent a countermeasure for astronauts subjected to microgravity-induced bone and muscle losses.

Highlights

We previously showed that Irisin, a myokine released from skeletal muscle after physical exercise, plays a central role in the control of bone mass
Hind-limb suspended mice were suspended and left untreated for 4 weeks and treated with vehicle or r-Irisin (100 μg kg−1 weekly) for the following 4 weeks of suspension. Results from these two groups of mice were compared to two control groups of mice, both treated with vehicle: rest mice, which were kept under normal loading, and reloaded mice, which were hindlimb-unloaded for 4 weeks followed by 4 weeks of re-ambulation with normal cage activities
Results of preventive and curative protocols have not been compared to each other. They have a different experimental timing because the preventive protocol was performed to investigate if irisin could inhibit disuse-induced bone loss, whereas the curative protocol was performed to investigate if irisin could restore a pre-existing bone loss caused by disuse

Summary

Introduction

We previously showed that Irisin, a myokine released from skeletal muscle after physical exercise, plays a central role in the control of bone mass. Data on fracture frequency in bedridden patients showed that 3.6% of 500 patients suffered from spontaneous fractures during a 6-year follow-up period[4], suggesting that disuse osteoporosis is a clinically relevant issue for its related morbidity and mortality as well as for health-care costs. Another well-documented unloading condition affecting the skeleton is the long exposure to microgravity during spaceflight. Skeletal muscle in elderly subjects suffering from impaired walking showed greater atrophy of Type IIx fibers and a decrease in myosin heavy chains IIα and IIx mRNA levels[12]

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