Overexpression of SIRT3(FL) Improves Cardiac SERCA2a Function Following High Fat-High Sucrose Feeding in Mice

Background Diabetes induces a distinct form of cardiomyopathy, termed diabetic cardiomyopathy (DCM). A key pathophysiological mechanism of DCM is reduced level and activity of sarco(endo)plasmic reticulum Ca 2+ ATPase 2a (SERCA2a). Recently, it has been discovered that the function of SERCA2a is negatively regulated by the post‐translational modification, acetylation. The sirtuin (SIRT) isoform, SIRT3 full‐length (SIRT3 FL ), deacetylates protein substrates, though it is unknown if SIRT3 FL deacetylates SERCA2a. Therefore, the objective of this study was to determine if the overexpression of SIRT3 FL alters cardiac SERCA2a acetylation and function in a mouse model of diabetes, induced by high fat‐high sucrose (HFHS) feeding. Methods and Results Adult (12 weeks of age) male C57BL/6J Wild Type (WT) mice and adult male MCK‐mSIRT3‐M1‐Flag transgenic (SIRT3 FL TG) mice on a C57BL/6J background, who overexpress the SIRT3 FL isoform in skeletal and cardiac muscle, were randomized into groups fed either a standard lab diet (Control) or a HFHS diet for 4‐months. After 4‐months, HFHS‐fed mice exhibited increased body weight, left ventricle (LV) weight, LV weight relative to body weight, and liver weight, compared to control fed‐mice. LV systolic parameters were unchanged by HFHS feeding, while the A and E wave forms of HFHS‐fed mice were slowed, compared to control‐fed mice. HFHS‐fed mice exhibited LV thickening, compared to control‐fed mice. Glucose tolerance was impaired in HFHS‐fed mice, compared to control‐fed mice. Diet did not alter SIRT3 protein content. Likewise, HFHS feeding did not alter the level or function of cardiac SERCA2a. LV SERCA2a protein content was not altered by genotype. However, SIRT3 FL TG mice, regardless of diet, had 21% greater maximal SERCA activity (V max ) and an 11% greater Hill coefficient, compared to WT mice. The Ca50, which is the Ca 2+ concentration that elicits 50% of V max , was 24% lower in SIRT3 FL TG‐HFHS‐fed mice, compared to WT‐HFHS‐fed mice, indicating an increase in Ca 2+ sensitivity. Conclusion HFHS feeding induced a diabetic phenotype in WT and SIRT3 FL TG mice but level and function of cardiac SERCA2a was unchanged. However, overexpression of the SIRT3 FL isoform improved cardiac SERCA2a function, regardless of HFHS feeding. Support or Funding Information This work was supported by a grant‐in‐aid from the Heart and Stroke Foundation of Canada