The role of the super-relaxed state of myosin in human metabolism

Abstract

Background The super-relaxed state of myosin (SRX) plays a fundamental role in maintaining the low resting metabolic rate of skeletal muscle. Our previous work on this state has been in animal models. Piperine is a small molecule that has been shown to destabilize the SRX in rabbit fast twitch fibers. Methods Here we extend this work to human muscle obtained from biopsies of the vastus lateralis of both lean and obese subjects. The slow release of nucleotides by myosin in the SRX was measured by incubating permeable fibers in a fluorescent analog of ATP and chasing with ATP. Results The fraction of myosin heads in the SRX was 0.48 ± 0.04 with a lifetime of 148 ± 5 s in lean subjects and a fraction of 0.41 ± 0.05 and a lifetime of 176 ± 7 s in obese subjects. Addition of 100 μM piperine decreased the SRX population by 43 ± 7% in lean subjects and 36 ± 7% in obese subjects, with little change in lifetimes. Addition of piperine to human cardiac cells had no effect on the SRX, a requirement for a drug to treat metabolic diseases. Conclusions In human muscle the SRX and its responses to piperine are similar to those seen previously, with no significant differences between muscles from lean and obese subjects. Thus analogs of piperine that have greater specificity could provide effective treatment for metabolic diseases. The SRX provides a potential mechanism contributing to the large dynamic range of metabolic rate.

Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle

“…The SRX state appears to be common to all mammalian striated muscle myosin and might serve a significant role in modulating muscle contractility ( Brunello et al, 2020 ). However, different muscle types show substantial differences in the overall proportion of SRX, evidenced by the twofold difference between the present data in mouse cardiac myofibrils compared with our previously published data ( Nelson et al, 2020 ) in slow-twitch, rat soleus (57 versus 28% SRX, respectively), although other studies have reported SRX content as high as 48% in human skeletal muscles ( Wilson et al, 2020 ). The higher SRX content in cardiac tissue may represent a unique aspect of cardiac myosin.…”

To lie or not to lie: Super-relaxing with myosins

“…However, piperine may not have the specificity needed for use in humans but might be a promising lead compound for discovering similar novel molecules that disrupt the myosin SRX state, thus activating the myosin molecule. Recently Wilson et al, 2021 showed that administration of piperine depopulated the myosin SRX state in human skeletal myosin obtained from biopsies of lean and obsese subjects, without affecting the human cardiac cells. These studies demonstrate that modulating myosin with small molecules to target the DRX↔SRX state equilibrium may be a novel avenue to treat muscle or metabolic disorders.…”

dATP Elevation Induces Myocardial Metabolic Remodeling to Support Improved Cardiac Function

“…Biochemical studies have shown that myosin heads (S1, Fig. 3a) are present in multiple physiological/conformational states in resting muscle, and these have different rates of ATP consumption which, in turn, when modulated (pathological mutation) can affect the overall CM metabolism 32,51 . Our recent study demonstrated that biochemically dATP pushes myosin heads from a low ATP consumption (SRX) to higher ATP consumption (DRX) state (Fig.…”