Toward countering muscle and bone loss with spaceflight: GSK3 as a potential target

Ryan W Baranowski; Jessica L Braun; Briana L Hockey; Jenalyn L Yumol; Mia S Geromella; Colton J F Watson; Nigel Kurgan; Holt N Messner; Kennedy C Whitley; Adam J MacNeil; Guillemette Gauquelin-Koch; Fabrice Bertile; William Gittings; Rene Vandenboom; Wendy E Ward; Val A Fajardo

doi:10.1016/j.isci.2023.107047

Toward countering muscle and bone loss with spaceflight: GSK3 as a potential target

iScience. 2023 Jun 8;26(7):107047. doi: 10.1016/j.isci.2023.107047. eCollection 2023 Jul 21.

Authors

Ryan W Baranowski^{1

2}, Jessica L Braun^{1

2}, Briana L Hockey^{1

2}, Jenalyn L Yumol^{1

2}, Mia S Geromella^{1

2}, Colton J F Watson³, Nigel Kurgan^{1

2}, Holt N Messner^{1

2}, Kennedy C Whitley^{1

2}, Adam J MacNeil³, Guillemette Gauquelin-Koch⁴, Fabrice Bertile⁵, William Gittings^{1

2}, Rene Vandenboom^{1

2}, Wendy E Ward^{1

2}, Val A Fajardo^{1

2}

Affiliations

¹ Department of Kinesiology, Brock University, St. Catharines, ON, Canada.
² Centre for Bone and Muscle Health, Brock University, St. Catharines, ON, Canada.
³ Department of Health Sciences, Brock University, St. Catharines, ON, Canada.
⁴ French Space Agency, Centre National d'Etudes Spatiales (CNES), Paris, France.
⁵ Hubert Curien Pluridisciplinary Institute (IPHC), CNRS, Strasbourg University, Strasbourg, France.

Abstract

We examined the effects of ∼30 days of spaceflight on glycogen synthase kinase 3 (GSK3) content and inhibitory serine phosphorylation in murine muscle and bone samples from four separate missions (BION-M1, rodent research [RR]1, RR9, and RR18). Spaceflight reduced GSK3β content across all missions, whereas its serine phosphorylation was elevated with RR18 and BION-M1. The reduction in GSK3β was linked to the reduction in type IIA fibers commonly observed with spaceflight as these fibers are particularly enriched with GSK3. We then tested the effects of inhibiting GSK3 before this fiber type shift, and we demonstrate that muscle-specific Gsk3 knockdown increased muscle mass, preserved muscle strength, and promoted the oxidative fiber type with Earth-based hindlimb unloading. In bone, GSK3 activation was enhanced after spaceflight; and strikingly, muscle-specific Gsk3 deletion increased bone mineral density in response to hindlimb unloading. Thus, future studies should test the effects of GSK3 inhibition during spaceflight.

Keywords: Musculoskeletal medicine; Space medicine.