Ang-(1-7) Protects Skeletal Muscle Function in Aged Mice

BACKGROUND The angiotensin-converting enzyme 2 (ACE2)/angiotensin 1-7 (Ang-(1-7)) axis has been shown to protect against the age-associated decline in skeletal muscle function. Here, we investigated the protective effects of ACE2 in mitigating the age-associated decline of skeletal muscle function and to identify the potential underlying molecular mechanisms. METHODS We measured the expression levels of Ang-(1-7) in C57BL/6J mice of different ages and correlated these levels with measures of skeletal muscle function. We also investigated the expression of myocyte enhancer factor 2 A (MEF2A) in ACE2 knockout (ACE2KO) mice and its relationship with muscle function. We then treated aged ACE2KO mice for four weeks with Ang-(1-7) and characterized the levels of MEF2A and skeletal muscle function before and after treatment. We assessed the impact of Ang-(1-7) on the growth and differentiation of C2C12 cells in vitro and assessed changes in expression of the glucose transporter type 4 (Glut4). RESULTS Aged mice showed reduced skeletal muscle function and levels of Ang-(1-7) expression in comparison to young and middle-aged mice. In ACE2KO mice, skeletal muscle function and MEF2A protein expression were significantly lower than in age-matched wild-type (WT) mice. After one month of Ang-(1-7) treatment, skeletal muscle function in the aged ACE2KO mice improved, while MEF2A protein expression was similar to that in the untreated group. In C2C12 cells, Ang-(1-7) was shown to promote along with the upregulated expression of Glut4. CONCLUSIONS The ACE2/ Ang-(1-7) axis has a protective function in skeletal muscle and administration of exogenous Ang-(1-7) can delay the age-related decline in the function of skeletal muscle.