Chapter 9 - myocardial insulin signaling and autophagy

Autophagy is a highly conserved catabolic mechanism that degrades and recycles senescent and damaged protein and cytosolic cargo in the lysosome to maintain metabolic, physiological, and functional homeostasis within cardiomyocytes. Autophagy is tightly regulated by cellular nutrient and mitogenic demand, of which extrinsic signaling substrates, such as insulin, facilitate and promote substrate utilization and cellular growth. Insulin is an evolutionarily conserved hormone that regulates glucose uptake and utilization in insulin-sensitive organs such as muscle, liver, and heart. Cardiomyocytes express the protein machinery necessary for insulin-induced responses such as energy metabolism, cellular growth and survival, calcium cycling, and contractility. We have described the processes of autophagy and insulin signaling, including recent novel mechanisms by which autophagy and insulin signaling regulate each other. At the molecular level, we have discussed autophagy’s relationship to critical steps in insulin signaling including initial signaling cascades, as well as the contribution of insulin receptor substrate (IRS) proteins, phosphatidylinositol 3-kinase (PI-3 K) and protein kinase B (Akt) on regulation of autophagic function. In addition, we have explained mechanisms by which insulin’s transcriptional effectors, including forkhead transcription factors (FOXO) proteins, regulate cardiac autophagy. We have also outlined the contribution of master transcriptional regulator of autophagy, TFEB, in insulin signaling outcomes. We have highlighted mechanisms by which dysregulated autophagy may lead to increased susceptibility to obesity, type 2 diabetes, hypertrophy, and diabetic cardiomyopathy. Overall, this book chapter summarizes existing knowledge concerning the role of autophagy and insulin signaling on metabolic and mitogenic processes in healthy and diseased hearts with emphasis on the regulatory connections and interplay between autophagy and insulin signaling axes.