Sirtuin 3 overexpression preserves maximal sarco(endo)plasmic reticulum calcium ATPase activity in the skeletal muscle of mice subjected to high fat-high sucrose-feeding

Abstract

Sarco(endo)plasmic reticulum calcium (Ca²⁺) ATPase (SERCA) transports Ca²⁺ in muscle. Impaired SERCA activity contributes to diabetic myopathy. Sirtuin (SIRT) 3 regulates muscle metabolism and function. However, it is unknown if SIRT3 regulates muscle SERCA activity. We determined if SIRT3 overexpression enhances SERCA activity in mouse gastrocnemius muscle and if SIRT3 overexpression preserves gastrocnemius SERCA activity in a model of type 2 diabetes, induced by high fat-high sucrose (HFHS)-feeding. We also determined if the acetylation status of SERCA proteins in mouse gastrocnemius is altered by SIRT3 overexpression or HFHS-feeding. Wild-type (WT) mice and SIRT3 transgenic (SIRT3_TG) mice, overexpressing SIRT3 in skeletal muscle, were fed a standard- or HFHS-diet for 4-months. SIRT3_TG and WT mice developed obesity and glucose intolerance after 4-months of HFHS-feeding. SERCA <i>V</i>_max was higher in gastrocnemius of SIRT3TG mice, compared to WT mice. HFHS-fed mice had lower SERCA1a protein levels and lower SERCA <i>V</i>_max in their gastrocnemius than control-fed mice. The decrease in SERCA <i>V</i>_max in gastrocnemius muscle due to HFHS-feeding was attenuated by SIRT3 overexpression in HFHS-fed SIRT3_TG mice. SERCA1a and SERCA2a acetylation in mouse gastrocnemius was not altered by genotype or diet. These findings suggest SIRT3 overexpression improves SERCA function in diabetic mouse skeletal muscle.