Physical activity impacts resting skeletal muscle myosin conformation and lowers its ATP consumption

Abstract

It has recently been established that myosin, the molecular motor protein, is able to exist in two conformations in relaxed skeletal muscle. These conformations are known as the super-relaxed (SRX) and disordered-relaxed (DRX) states and are finely balanced to optimize ATP consumption and skeletal muscle metabolism. Indeed, SRX myosins are thought to have a 5- to 10-fold reduction in ATP turnover compared with DRX myosins. Here, we investigated whether chronic physical activity in humans would be associated with changes in the proportions of SRX and DRX skeletal myosins. For that, we isolated muscle fibers from young men of various physical activity levels (sedentary, moderately physically active, endurance-trained, and strength-trained athletes) and ran a loaded Mant-ATP chase protocol. We observed that in moderately physically active individuals, the amount of myosin molecules in the SRX state in type II muscle fibers was significantly greater than in age-matched sedentary individuals. In parallel, we did not find any difference in the proportions of SRX and DRX myosins in myofibers between highly endurance- and strength-trained athletes. We did however observe changes in their ATP turnover time. Altogether, these results indicate that physical activity level and training type can influence the resting skeletal muscle myosin dynamics. Our findings also emphasize that environmental stimuli such as exercise have the potential to rewire the molecular metabolism of human skeletal muscle through myosin.

Remodeling of skeletal muscle myosin metabolic states in hibernating mammals

“…Our findings demonstrate that in small hibernators such as I. tridecemlineatus and E. quercinus , the ATP turnover time of relaxed myosin molecules (in both DRX and SRX conformations) is faster during torpor (and IBA), especially in type II muscle fibers, leading to an unexpected overall increased ATP consumption. Accordingly, a few studies investigating human pathological conditions have reported disruptions of the myosin ATP turnover times in resting isolated skeletal myofibers, but their actual impacts have never been thoroughly investigated ( Lewis et al, 2023 ; Phung et al, 2020 ; Sonne et al, 2023 ). Here, originally, we estimated the consequences on the actual energy consumption of sarcomeres/muscle fibers.…”

Dysregulated Skeletal Muscle Myosin Super-relaxation and Energetics in Type II Diabetes

“…However, much of the early work on resting myosin head biophysics has been concentrated on cardiac diseases and in particular, hypertrophic cardiomyopathy, an inherited disease caused by mutations to sarcomeric proteins 13, 20–23 . It is only recently that we have demonstrated that myosin biochemical states are dynamic and greatly influenced by non-genetic factors 44, 45 . Thus, based on these findings, investigating the potential involvement of changes to the dynamics of myosin in cardiometabolic syndromes such as T2DM was an obvious next step.…”

“…Their ends were individually clamped to half-split copper meshes designed for electron microscopy (SPI G100 2010C-XA, width, 3 mm), which had been glued to glass microscopy slides (Academy, 26 x 76 mm, thickness 1.00-1.20 mm). Cover slips were then secured to the top of the slide to create a flow chamber (Menzel-Gläser, 22 x 22 mm, thickness 0.13-0.16 mm) 44, 73 . Subsequently, at 20°C, myofibers with a sarcomere length of 2.00 μm were surgically mounted onto the copper mesh (assessed using the brightfield mode of a Zeiss Axio Scope A1 microscope).…”

Remodelling of skeletal muscle myosin metabolic states in hibernating mammals

“…Our findings demonstrate that in small hibernators such as I. tridecemlineatus and E. quercinus , the ATP turnover time of relaxed myosin molecules (in both DRX and SRX conformations) is faster during torpor (and IBA), especially in type II muscle fibers, leading to an unexpected overall increased ATP consumption. Accordingly, a few studies investigating human pathological conditions have reported disruptions of the myosin ATP turnover times in resting isolated skeletal myofibers, but their actual impacts have never been thoroughly investigated [45–47]. Here, originally, we estimated the consequences on the actual energy consumption of sarcomeres/muscle fibers.…”