Myosin Super-relaxed State is Affected by Aging in Female But Not Male Skeletal Muscle

Abstract

Muscle weakness is consistently reported as an independent risk factor for high mortality in aged individuals. In aging females, ovarian hormone deficiency that occurs during menopause has a role in the loss of skeletal muscle strength. At the molecular level, the loss of muscle force production may be attributed to the slowing of myosin-actin cross-bridge kinetics and different structural states of the myosin head is key. There are three distinct functional states of the myosin head: active state, relaxed state (RX) and super-relaxed state (SRX). The SRX state is emerging as an important factor in muscle mechanics and regulation, yet its possible role in aging process has remained elusive. A previous study showed that estradiol-mediated signaling reversibly regulated ATP turnover in SRX state, which in turn may contribute to the age-related decline in muscle strength and function in females. PURPOSE: To further evaluate the role of ovarian hormones in SRX regulation during aging, we measured the SRX population and ATP turnover rate in skeletal muscle fibers from female and male mice during natural aging process. METHODS: The population of myosin heads in the SRX state and ATP turnover rate were measured in chemically skinned skeletal muscle (psoas) fibers from young (3-4 months old) and aged (28 months old) C57BL/6 female and male mice. Quantitative confocal microscopy of fluorescent MANT-ATP turnover was used to detect and quantitate myosin SRX in the fibers. RESULTS: In female mice, fibers from aged animals had faster SRX and RX myosin ATP turnover rates compared to those from young mice (SRX: 94 ± 6s vs 117 ± 9s, p = 0.033 and RX: 18 ± 1s vs 25 ± 2s, p < 0.001). There was no difference in turnover rates between fibers from young and aged male mice (SRX: p = 0.804 and RX: p = 0.202). We found no differences in the population of myosin heads in RX and SRX states between young and aged fibers in either sex (p ≥ 0.100). CONCLUSION: Our results indicate that ovarian hormones rather than aging process per se influence the myosin SRX state. This work was supported by R01-AR032961, R37-AG26160, T32-AR007612, and R01-AG031743.