Effects of ACE2 deficiency on physical performance and physiological adaptations of cardiac and skeletal muscle to exercise

Abstract

The renin-angiotensin system (RAS) is related to physiological adaptations induced by exercise. Angiotensin-converting enzyme (ACE) 2 is a major regulator of the RAS in tissues, as it metabolizes angiotensin (Ang) II to Ang-(1-7). The aim of this study was to determine the effects of ACE2 deficiency on physical performance and physiological adaptations induced by voluntary running. Physical performance, body composition and plasma angiotensin levels, as well as tissue morphology and gene expression of RAS components in the left ventricle (LV) and skeletal muscle (gastrocnemius), were evaluated in ACE2-deficient (ACE2(-/y)) and wild-type (ACE2(+/y)) mice after 6 weeks of voluntary wheel running. ACE2(-/y) mice run less than ACE2(+/y) mice (19±4.7 vs. 26±12.6 revolutions per day × 100, P<0.01). The ACE2(+/y) group presented a lower fat mass (15±1.1%) and higher muscle mass (76.6±1.6%) after 6 weeks of voluntary running compared with the sedentary control group (fat mass: 18.3±2.1%; muscle mass: 72.7±2.2). However, no change in body composition was observed in ACE2(-/y) mice after exercise. Heart and skeletal muscle hypertrophy was observed only in trained ACE2(+/y) mice. Besides a small decrease in Ang I in ACE2(-/y) mice, plasma levels of angiotensin peptides remained unchanged by exercise or ACE2 deficiency. In the LV of trained animals, AT2 gene expression was higher in ACE2(+/y) compared with ACE2(-/y) mice. ACE2 deficiency leads to an increase in AT1 gene expression in skeletal muscle. ACE expression in soleus was increased in all exercised groups. ACE2 deficiency affects physical performance and impairs cardiac and skeletal muscle adaptations to exercise.

Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response

“…Although running less, ACE2-deficient mice in our study ran continuously every night. As shown for WT mice, long-term voluntary wheel running leads to alterations in muscle strength (e.g., increased muscle mass and skeletal muscle hypertrophy) that was abolished in ACE2-deficient mice [34]. Skeletal muscle releases cathepsin B during longterm treadmill running in monkeys that might affect brain function [35].…”

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

“…Riquelme et al (446) suggested that the expression of ACE2 regulates fibrosis in dystrophic muscle since muscle damage causes increased activity of ACE2, and ACE2 levels correlate with the degree of fibrosis. Recently it has been reported that ACE2 -/y mice show reduced performance in voluntary running (380), but it is unknown whether this is a result of the genetic deletion of ACE2 in muscle cells, considering that this mouse exhibits an overall deficiency in ACE2.…”

ACE2 in Brain Physiology and Pathophysiology: Evidence from Transgenic Animal Models

“…This review will summarize how animals with targeted alterations in ACE2 expression have helped to reveal its physiological and pathophysiological functions in particular in the central nervous system. The same and additional models have also been used to discover that ACE2 is a major determinant in cardiac [24,[30][31][32] and vascular function [33][34][35], atherosclerosis [36][37][38][39], metabolism [37,40], kidney [41][42][43][44] and lung diseases [45,46], to only name a few. However, these peripheral actions of ACE2 have previously been reviewed and are therefore not subject of this paper [19,[47][48][49][50].…”