Insulin and Insulin-Like Growth Factor 1 Signaling Preserves Sarcomere Integrity in the Adult Heart

ABSTRACT

Insulin and insulin-like growth factor 1 (IGF1) signaling is transduced by insulin receptor substrate 1 (IRS1) and IRS2. To elucidate physiological and redundant roles of insulin and IGF1 signaling in adult hearts, we generated mice with inducible cardiomyocyte-specific deletion of insulin and IGF1 receptors or IRS1 and IRS2. Both models developed dilated cardiomyopathy, and most mice died by 8 weeks post-gene deletion. Heart failure was characterized by cardiomyocyte loss and disarray, increased proapoptotic signaling, and increased autophagy. Suppression of autophagy by activating mTOR signaling did not prevent heart failure. Transcriptional profiling revealed reduced serum response factor (SRF) transcriptional activity and decreased mRNA levels of genes encoding sarcomere and gap junction proteins as early as 3 days post-gene deletion, in concert with ultrastructural evidence of sarcomere disruption and intercalated discs within 1 week after gene deletion. These data confirm conserved roles for constitutive insulin and IGF1 signaling in suppressing autophagic and apoptotic signaling in the adult heart. The present study also identifies an unexpected role for insulin and IGF1 signaling in regulating an SRF-mediated transcriptional program, which maintains expression of genes encoding proteins that support sarcomere integrity in the adult heart, reduction of which results in rapid development of heart failure.

KEYWORDS:

• heart failure
• cardiac remodeling
• insulin signaling
• cardiac structure

Declaration of Interests

The authors declare no conflict of interest.

SUPPLEMENTAL MATERIAL

Supplemental material is available online only.

ACKNOWLEDGMENTS

We thank Kathy Zimmerman (mouse cardiovascular phenotyping core at the University of Iowa) for technical assistance.

This work was supported by National Institutes of Health grants R01HL127764, R01HL112413, R01HL108379, and R01DK092065 to E.D.A., who is an established investigator of the American Heart Association. R.L.B. has received research support from National Institutes of Health (NHLBI) grants R01-HL144717, R01-HL148796, and R01-HL150557. The mouse cardiovascular phenotyping core at the University of Iowa is supported by NIH instrumentation grant OD019941 to R.M.W. C.R. was supported by a postdoctoral fellowship from the German Research Foundation (DFG). Figure 6 was produced using templates from Servier Medical Art (https://smart.servier.com).