ATP Consumption by Sarcoplasmic Reticulum Ca(2+) Pumps Accounts for 40-50% of Resting Metabolic Rate in Mouse Fast and Slow Twitch Skeletal Muscle

The main purpose of this study was to directly quantify the relative contribution of Ca(2+) cycling to resting metabolic rate in mouse fast (extensor digitorum longus, EDL) and slow (soleus) twitch skeletal muscle. Resting oxygen consumption of isolated muscles (VO(2), µL/g wet weight/s) measured polarographically at 30(°)C was ~20% higher (P<0.05) in soleus (0.326 ± 0.022) than in EDL (0.261 ± 0.020). In order to quantify the specific contribution of Ca(2+) cycling to resting metabolic rate, the concentration of MgCl(2) in the bath was increased to 10 mM to block Ca(2+) release through the ryanodine receptor, thus eliminating a major source of Ca(2+) leak from the sarcoplasmic reticulum (SR), and thereby indirectly inhibiting the activity of the sarco(endo) plasmic reticulum Ca(2+)-ATPases (SERCAs). The relative (%) reduction in muscle VO(2) in response to 10 mM MgCl(2) was similar between soleus (48.0±3.7) and EDL (42.4±3.2). Using a different approach, we attempted to directly inhibit SERCA ATPase activity in stretched EDL and soleus muscles (1.42x optimum length) using the specific SERCA inhibitor cyclopiazonic acid (CPA, up to 160 µM), but were unsuccessful in removing the energetic cost of Ca(2+) cycling in resting isolated muscles. The results of the MgCl(2) experiments indicate that ATP consumption by SERCAs is responsible for 40–50% of resting metabolic rate in both mouse fast- and slow-twitch muscles at 30(°)C, or 12–15% of whole body resting VO(2). Thus, SERCA pumps in skeletal muscle could represent an important control point for energy balance regulation and a potential target for metabolic alterations to oppose obesity.