Abstract 257: PP2Cm Regulation Links Branched Chain Amino Acid with Hypertrophy Response

[Introduction] Branched Chain Amino Acids (BCAAs), including leucine, isoleucine, and valine, modulate mTOR activity that controls protein synthesis and cell growth. PP2Cm is a mitochondrial protein phosphatase that regulates the rate limiting step of BCAA degradation. Loss of PP2Cm leads to BCAA accumulation. [Hypothesis] PP2Cm downregulation by hypertrophic signal impairs BCAA catabolism and thus hypertrophy response in heart. [Methods and Results] High level of PP2Cm is expressed in heart through all development stages. PP2Cm expression was reduced in hypertrophic heart induced by pressure overload, corresponding with increase of BCAA level and mTOR activity. KLF15 and microRNA22 are both key regulators of hypertrophy. It has been shown that hypertrophy signal s upregulated microRNA22 while decreasing KLF15 expression. We found that KLF15 increased PP2Cm promoter activity and miRNA22 regulated PP2Cm mRNA level and protein expression via 3’UTR . Together, our data indicated that hypertrophy inducers down-regulates KLF15 while increasing miRNA22, resulting in decreased PP2Cm level and thus repressed BCAA catabolism, which in turn can impact on mTOR mediated signaling and activity. [Conclusions] Pathological stress may affect the expression of PP2Cm and influence the outcome of hypertrophic response, suggesting an important role of BCAA nutrient and PP2Cm expression in heart.