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 may contribute to diabetic myopathy. Sirtuin (SIRT) 3 regulates muscle metabolism and function; however, it is unknown if SIRT3 regulates muscle SERCA activity or acetylation. 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) 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 V_max was higher in gastrocnemius of SIRT3_TG mice compared with WT mice. HFHS-fed mice had lower SERCA1a protein levels and lower SERCA V_max in their gastrocnemius than control-fed mice. The decrease in SERCA V_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 mouse skeletal muscle.

Keywords: SERCA; acetylation; acétylation; calcium handling; diabetes; diabète; manipulation du calcium; muscle; sirtuines; sirtuins.