MUTUAL COMPLEMENTALLY RELATIONSHIP OF AT2 AND MAS RECEPTORS IN PROTECTIVE EFFECT AGAINST SKELETAL MUSCLE AGEING IN MICE

Abstract

Objective: Increasing evidence suggests that the renin-angiotensin system (RAS) is a candidate for control aging-associated phenotypes. RAS have two distinct axes, which counter-regulate each other. One is canonical RAS axis composed of angiotensin II and AT1 receptor, another is non-canonical RAS axis, it's main components are angiotensin 1–7 and AT2 and Mas receptors. To elucidate whether non-canonical axis have protective effect against age-associated muscle weakness, we first tested with Mas KO mice. But we didn’t any significant difference in aging phenotype in Mas KO mice compared with wild-type (WT) mice (Clinical Science, 2019.). In this study, we focused on AT2 receptor, we tested skeletal muscle function of AT2 KO mice and AT2 / Mas double KO (DKO) mice. Design and method: AT2 KO mice, DKO mice and WT mice were used (n = 5–8). To assess serial change in motor function, we performed grip strength test in 6, 12, 18, 24 months old. At 24 months old, mice were sacrificed and extracted six kinds of skeletal muscles. Using skeletal muscles, wet weight, cross sectional area of myofiber, expression of RAS-associated, inflammatory-associated and senescence-associated genes were assessed. All of data are statically analyzed by using Dunnett's test. Results: DKO mice showed significant weaker grip strength than WT mice from the age of 18 months. Wet weights of soleus and Vastus muscle were lower in DKO than WT mice. Classical RAS associated genes (Renin, ACE, AT1), inflammatory-associated genes (MCP-1, IL-6, TGF beta-1) and senescence-associated genes (p16, p19) is highly expressed in vastus of DKO. Grip strength, wet weight of skeletal muscles, and gene expression levels in AT2KO mice are equivalent to WT mice. Cross sectional area of vastus myofiber is significantly lower in AT2KO and DKO than in WT. Conclusions: In summary, we observed exaggerated ageing phenotypes of skeletal muscles in DKO mice, while hardly any ageing phenotypes were observed neither in AT2KO mice nor Mas KO mice. Our data suggests AT2 and Mas receptors are mutual complementally relationship in protective roll against age-associated skeletal muscle weakness via blockade of canonical RAS axis.