The Super Relaxed State of Myosin in Human Muscle

Abstract

The Super Relaxed State of myosin (SRX) plays a role in maintaining the low resting metabolic rate of skeletal muscle. Pharmaceuticals that destabilize this state could increase resting muscle and whole body metabolic rate by as much as 1000 Calories/day, providing an effective treatment for obesity and type 2 diabetes. Our previous work on this state in skeletal muscle has all been in animal models. Here we extend this approach to human muscle. Biopsies from the quadriceps lateralis of both lean and obese subjects were used. Measurements of single turnovers showed an SRX with a population of 0.27 ± 0.02 and a lifetime of 150 ± 8 sec in lean subjects and a population of 0.28 ± 0.02 and a lifetime of 158 ± 10 sec in obese subjects. Piperine is a small molecule that has been shown to destabilize the SRX in rabbit fast twitch fibers, with no effect on slow twitch fibers. In human muscle, addition 100μM piperine reduced the population of the SRX by 34% in lean subjects and 25% in obese subjects, with little change in the lifetimes. The human quadriceps lateralis contains ∼50% fast twitch and ∼50% slow twitch fibers. Data obtained with piperine showed two responses with ∼50% of fibers showing a strong inhibition of the SRX and the remaining fibers showing very little, in both lean and obese subjects. Presumably the fibers showing strong inhibition are fast twitch, but this remains to be proven. We conclude that in human muscle the SRX and its response to piperine are similar to those seen previously in rabbit muscle, with little difference between lean and obese subjects. This shows that analogs of piperine that have higher affinity would provide effective treatment for metabolic diseases.