An emerging feature of cardiometabolic disease states, including obesity, diabetes, and heart failure is perturbed
metabolism and subsequent elevations of plasma branched-chain amino acids (BCAA; valine, leucine,
isoleucine) and their cognate a-ketoacids (BCKA; KIV, KIC, KMV). Work from our group and others has revealed
that elevated plasma BCKA arise in these conditions due to impaired activity of the branched chain a-ketoacid
dehydrogenase (BCKDH) complex in liver, resulting from higher expression of the inhibitory BCKDH kinase,
BDK, and lower expression of the activating phosphatase, PPM1K. Importantly, whole-body manipulation of
BCKA metabolism achieved via pharmacologic or genetic modulation of BDK and PPM1K yields robust impacts
on cardiac structure, function, and metabolism. Thus, novel therapeutic approaches targeting BCKA-related
pathways hold significant potential for treatment of cardiac dysfunction. However, it remains unclear whether
the in vivo effects of systemic BDK and PPM1K manipulation on cardiac function are due to modulation of
PPM1K and BDK activity within the heart or simply the result of chronic exposure of the heart to increased
plasma BCKA. The work outlined in this proposal will build upon our prior work to directly address this important
knowledge gap by leveraging newly developed animal models to: 1) Determine the impact of liver-specific BDK
modulation on cardiac function; 2) Extend our mechanistic understanding of BCKA-mediated signal transduction
pathways in the heart; and 3) Define the role of PPM1K in the heart. The knowledge gained from the completion
of this project is expected to aid in development of BCKA-related therapeutic targets for the treatment of cardiac
dysfunction in a wide range of cardiometabolic diseases.