Cardiac myocyte-specific expression of beta3-adrenergic receptors sustains AMPK activation and glucose uptake while reducing hypertrophy following pressure overload

Introduction Cardiac beta3-adrenergic receptors (B3AR) produce effects antipathetic to those of B1 and B2 receptors. Importantly, B3AR are resistant to desensitization and their expression is upregulated in the diseased myocardium. We previously showed that mice with moderate cardiac-specific expression of the human B3AR (B3-TG) are protected from hypertrophy and fibrosis upon hemodynamic or neurohormonal stress. Objective Here we tested the hypothesis that myocardial protection may be mediated by metabolic effects of B3AR in cardiac myocytes, akin to well-known B3AR metabolic effects in adipose tissue. Method We used both B3-TG mice (and WT littermate) and isolated adult cardiac myocytes exposed to hemodynamic overload (TAC) (or sham control). Results We found that 9 week-TAC induced hypertrophy and fibrosis in WT mice, as expected. Notably this was paralleled with decreased activation of AMPK assessed by AMPK phosphorylation at Thr-172 and phosphorylation of its downstream target ACC. However, in B3-TG mice AMPK activation was preserved post TAC. Moreover, siRNA downregulation of alpha1/2 AMPK attenuated the protection from hypertrophy by B3AR expression, confirming AMPK implication in the B3AR control of hypertrophy. As cardiac AMPK controls metabolic substrate use and uptake, we examined glucose uptake in adult cardiac myocytes isolated from B3-TG (and WT) mice after TAC, with/without insulin. Cardiac myocytes from stressed B3-TG mice exhibited a significant increase in 2-3H glucose uptake upon insulin treatment, whereas WT myocytes developed insulinoresistance. In vivo B3-TG also exhibited an increased myocardial uptake of the glucose analog 18FDG compared to WT littermates, e.g. at 9 weeks post-TAC. Conclusion We conclude that cardiac myocyte-specific expression of B3AR concurrently prevents the development of insulin resistance and maintains AMPK activation contributing to the protection from hypertrophic remodeling under hemodynamic stress.