Abstract
BackgroundThe 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.MethodsWe 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).ResultsAged 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.ConclusionsThe 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.
Highlights
The process of aging is correlated with pronounced decreases in skeletal muscle mass, reduced muscular function and a general decline in physical fitness
These data indicated that the function of mouse skeletal muscle and the expression of Ang-(1–7) were both reduced with aging
Previous findings have shown that the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II) axis is correlated with skeletal muscle insulin resistance, atrophy and fibrosis and antagonizes the angiotensin-converting enzyme 2 (ACE2)/Ang-(1–7) axis [12, 13]
Summary
The process of aging is correlated with pronounced decreases in skeletal muscle mass, reduced muscular function and a general decline in physical fitness. In the clinic, these manifestations are commonly associated with sarcopenia and frailty [1]. The association between RAS and the angiotensin-converting enzyme (ACE)-angiotensin II (Ang II) axis is well documented. The main pathological features of sarcopenia are directly related to the age-related decline in the mass and structure of skeletal muscles and the ACE/Ang II pathway has been found to be closely associated with skeletal muscle loss [5]. 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. 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
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