Involvement of receptor for advanced glycation end products in microgravity-induced skeletal muscle atrophy in mice

Abstract

The accumulation of advanced glycation end-products (AGEs) may be involved in the mechanism of skeletal muscle atrophy. However, the involvement of the receptor for AGEs (RAGE) axis in microgravity-induced skeletal muscle atrophy has not been investigated. Therefore, the purpose of the present study was to investigate the effect of RAGE inhibition on microgravity-induced skeletal muscle atrophy and the related molecular responses. Male C57BL/6NCr mice subjected to a 1-week hindlimb suspension lead to muscle atrophy in soleus and plantaris but not extensor digitorum longus muscle, accompanied by increases in RAGE expression. However, treatment with a RAGE antagonist (FPS-ZM1, intraperitoneal, 1 mg/kg/day) during hindlimb suspension ameliorated the atrophic responses in soleus muscle. Further, muscle mass inversely correlated with the accumulation of AGEs (methylglyoxal-modified proteins and Nε-(carboxymethyl) lysine-modified proteins) in soleus muscle. The expression of proinflammatory cytokines, tumor necrosis factor-α, interleukin-1β, and interleukin-6 in soleus muscle was enhanced in response to hindlimb suspension, but these changes were attenuated by FPS-ZM1 treatment. Protein ubiquitination and ubiquitin E3 ligase (muscle RING finger 1) expression in soleus muscle were elevated following hindlimb suspension, and these increments were suppressed by FPS-ZM1 treatment. Our findings indicate that the AGE-RAGE axis is upregulated in unloaded atrophied skeletal muscle, and that RAGE inhibition ameliorates microgravity-induced skeletal muscle atrophy by reducing proinflammatory cytokine expression and ubiquitin-proteasome system activation.