Muscle‐specific sirtuin 3 overexpression does not attenuate the pathological effects of high‐fat/high‐sucrose feeding but does enhance cardiac SERCA2a activity

Obesity, type 2 diabetes, and heart disease are linked to an unhealthy diet. Sarco(endo)plasmic reticulum calcium (Ca 2+ ) ATPase 2a (SERCA2a) controls cardiac function by transporting Ca 2+ in cardiomyocytes. SERCA2a is altered by diet and acetylation, independently; however, it is unknown if diet alters cardiac SERCA2a acetylation. Sirtuin (SIRT) 3 is an enzyme that might preserve health under conditions of macronutrient excess by modulating metabolism via regulating deacetylation of target proteins. Our objectives were to determine if muscle‐specific SIRT3 overexpression attenuates the pathological effects of high fat‐high sucrose (HFHS) feeding and if HFHS feeding alters cardiac SERCA2a acetylation. We also determined if SIRT3 alters cardiac SERCA2a acetylation and regulates cardiac SERCA2a activity. C57BL/6J wild‐type (WT) mice and MCK‐mSIRT3‐M1‐Flag transgenic (SIRT3 TG ) mice, overexpressing SIRT3 in cardiac and skeletal muscle, were fed a standard‐diet or a HFHS‐diet for 4 months. SIRT3 TG and WT mice developed obesity, glucose intolerance, cardiac dysfunction, and pathological cardiac remodeling after 4 months of HFHS feeding, indicating muscle‐specific SIRT3 overexpression does not attenuate the pathological effects of HFHS‐feeding. Overall cardiac lysine acetylation was increased by 63% in HFHS‐fed mice ( p  = 0.022), though HFHS feeding did not alter cardiac SERCA2a acetylation. Cardiac SERCA2a acetylation was not altered by SIRT3 overexpression, whereas SERCA2a V max was 21% higher in SIRT3 TG ( p  = 0.039) than WT mice. This suggests that SIRT3 overexpression enhanced cardiac SERCA2a activity without direct SERCA2a deacetylation. Muscle‐specific SIRT3 overexpression may not prevent the complications associated with an unhealthy diet in mice, but it appears to enhance SERCA2a activity in the mouse heart.