Sarcolipin Ablation Increases Ca2+ Pump Efficiency in Mouse Skeletal Muscle

Abstract

Reconstitution experiments have shown that sarcolipin (SLN) uncouples ATP hydrolysis from Ca2+ transport by SR Ca2+ pumps and increases the amount of heat released per mol of ATP hydrolyzed by causing an increased rate of “slippage” on Ca2+ pumps. In this study, we analyzed skeletal muscle Ca2+ pump activity in the presence and absence of the Ca2+ ionophore A23187 (iono) and Ca2+ uptake without oxalate in SLN null mice (KO) to determine whether SLN uncouples ATP hydrolysis from Ca2+ transport in vivo. In 3 muscles analyzed (soleus (Sol), EDL, gastrocnemius (G)), there were no differences in maximal Ca2+ pump activity measured in homogenates (hom) with iono between KO and wildtype mice (WT). In Sol, but not EDL or G, there was an increased Ca2+ pump affinity for Ca2+ in KO as demonstrated by a leftward shift in the Ca2+ pump activity‐pCa curves. Ca2+ pump activity measured in the absence of iono was ~15–25% lower in all KO muscles compared with WT which is consistent with the idea that SLN increases “slippage” and reduces the extent of back‐inhibition on Ca2+ pumps. In the only muscle analyzed (Sol), Ca2+ uptake measured in hom without oxalate was not different between KO and WT which means Ca2+ transport efficiency in KO was increased ~19%. These results show that at a physiological SLN:Ca2+ pump ratio, SLN uncouples ATP hydrolysis from SR Ca2+ uptake in skeletal muscle. Supported by NSERC (ART), HSFO (DHM, PHB, AOG) and CIHR (DHM, PHB).