SLN overexpression upregulates mitochondrial dynamics and promotes oxidative metabolism during caloric restriction.

Abstract

Obesity results from increased caloric intake, physical inactivity and is a major contributor to type 2 diabetes (T2D). Exercise and caloric restriction (CR) are the most effective interventions to prevent obesity, T2D and sarcopenia. By increasing fatty acid oxidation (FAO), CR promotes insulin sensitivity and improves mitochondrial function. Our laboratory has identified Sarcolipin (SLN) as an important player in muscle thermogenesis. SLN‐binding to SERCA promotes uncoupling of Ca2+ transport, causing futile cycling of the SERCA pump, increasing energy expenditure. SLN overexpression in glycolytic muscle leads to increased mitochondrial biogenesis and FAO, resembling an oxidative phenotype. Therefore, we sought to determine if SLN overexpression (1) promotes resistance to fatigue and increased exercise performance and (2) improves the beneficial effects of CR in skeletal muscle mitochondrial metabolism. Wild type (WT), Sarcolipin knockout (SLN−/−) and Sarcolipin overexpression (SLNOE) mice were submitted to 8 weeks of exercise training at 60% of maximal effort capacity. After exercise, oxygen consumption, maximal force and resistance to fatigue were measured in isolated muscles. Electronic transport chain (ETC) and oxidative phosphorylation (OXPHOS) related proteins were analyzed in muscle and adipose tissue. Exercise‐induced increase in ETC proteins of white adipose tissue was blunted in SLN−/− mice. Our results show that SLNOE are resistant to fatigue and show better functional recovery as compared with WT and SLN−/−. Oxygen consumption is also increased in tibialis anterior after exercise in SLNOE, indicating that SLN overexpression in glycolytic muscle improves FAO and promotes endurance capacity. To induce CR, 3 month‐old male WT, SLN−/− and SLNOE mice were submitted to 8 weeks of 40% CR protocol, and body weight was measured weekly. Glucose tolerance test and insulin sensitivity measurements showed that SLNOE improved CR‐induced insulin sensitivity and glucose tolerance. Western blot analysis revealed that CR‐induced increase in ETC proteins (Complex I to V) and mitochondrial content (Tfam) is SLN‐dependent. Secondly, SLN increases mitochondrial fusion (Mfn1 and Opa1) and fission (Drp1) proteins and, as expected, CR increased markers of autophagy (LC3‐ II). Our data indicates that SLN plays an important role in metabolic adaptations in muscle by modulating mitochondrial dynamics and promoting oxidative metabolism. We propose that SLN can contribute to CR induced metabolic benefits in muscle.Support or Funding InformationNIDDK ‐R01 DK098240This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.