Angiotensin II receptor blockade protects against the slow to fast fiber type shift and type I fiber atrophy in the rat soleus with 7 days of hindlimb unloading (LB804)

Abstract

Reduced mechanical loading during spaceflight and immobilization results in weakening and atrophy of antigravity skeletal muscles. Data indicates that oxidative stress contributes to inactivity‐induced muscle atrophy. Recently we observed that the Nox2 isoform of NADPH oxidase is upregulated during unloading‐induced soleus muscle atrophy. Clues from other tissue types indicate activation of angiotensin II type 1 receptor (AT1R) as an upstream event leading to Nox2 complex formation and activity. Here, we used an AT1R blocker (Losartan) to test the hypothesis that AT1R activation is an upstream signaling event driving Nox2 complex activity, and thus atrophy in the mechanically unloaded soleus. Rats were divided into 4 groups: ambulatory control (CON), ambulatory + Losartan (40 mg/kd/day) (CON‐L), hindlimb unloaded for 7 days (HU), and HU + Losartan (HU‐L). Losartan treatment did not protect against the reduction in soleus mass during 7 days of unloading. However, the increase in Type II muscle fibers seen with unloading was mitigated by Losartan administration. Losartan also protected against atrophy of Type I muscle fibers. In addition, Losartan reduced the signal intensity and membrane localization of the Nox2 subunit p67phox in the unloaded soleus. Our findings suggest a potential role of AT1R activation as an upstream signaling event leading to Nox2 complex formation, activation, and slow to fast fiber‐type shift during mechanical unloading.Grant Funding Source: Supported by NASA (NNX13AE45G), Predoctoral Space Physiology Grant from ACSM/NASA, and the Sydney and J.L. Huffines Institute