Sarcolipin overexpression in mice increases their endurance exercise capacity (1162.2)

Abstract

Sarcolipin (SLN) is a transmembrane protein that interacts with Sarco(endo)plasmic Reticulum Calcium ATPase (SERCA) and is expressed in cardiac and skeletal muscle. SLN is known to inhibit Vmax of SERCA, but its role in muscle physiology is yet to be fully understood. We have shed some light on this front, by showing that SLN knock out (SLN KO) mice are highly sensitive to acute cold and are prone to develop obesity when fed a high fat diet. Moreover, we showed that the SLN KO mice can be rescued from hypothermia by over expression of the SLN transgene; suggesting that SLN is essential for heat generation and increasing metabolic rate. The aim of this study was to further explore how SLN affects muscle function and metabolism; by the use of SLN over expression (SLN OE) mouse model, which expresses SLN in all skeletal muscles up to 10 fold higher than in wild type (WT) mice. Here, we show that SLN OE mice have a higher basal metabolic rate (by indirect calorimetry) than WT mice. The SLN OE mice also have a significantly higher endurance capacity (treadmill running) than their WT littermates. Isolated muscle studies using Tissue Oxygen bath system, show that SLN OE muscle has similar force frequency response as WT muscle, but is more resistant to develop fatigue and consumes more oxygen. Analysis of muscle oxidative metabolic markers and oxygraph measurements using isolated mitochondria; suggest an increased oxidative capacity in the SLN OE muscle compared to WT. Although skeletal muscle can increase metabolic rate up to hundred fold, a decline in the rate of ATP production is a major reason for muscle fatigue during prolonged physical activity. Hence, these results indicate that SLN enhances muscle’s ability to hydrolyze substrates and generate ATP in times of increased energy demand, which in turn increases endurance capacity.Grant Funding Source: Supported by NIH