After years of intense research using structural, biological, and biochemical experimental procedures, it is clear that myosin molecules are essential for striated muscle contraction. However, this is just the tip of the iceberg of their function. Interestingly, recently, it has been shown that these molecules (especially myosin heavy chains) are also crucial for cardiac and skeletal muscle relaxed state. In the present review, we first overview myosin heavy chain biochemical states and how they influence the consumption of ATP. We then detail how neighbouring partner proteins including myosin light chains and myosin binding protein C intervene in such processes, modulating energy demand in health and disease. Finally, we present current experimental drugs targeting myosin ATP consumption and how they can treat muscle diseases.

Dilated cardiomyopathy (DCM) is a naturally occurring heart failure condition in humans and dogs, notably characterized by a reduced ejection fraction. As the identification of the underlying cellular and molecular mechanisms remain incomplete, the aim of the present study was to assess whether myosin and its known relaxed conformational states contribute to DCM aetiology. For that, we dissected and skinned thin cardiac strips from left ventricle obtained from six DCM Doberman Pinschers and six nonfailing controls (NF). We then used Mant-ATP chase experiments, X-ray diffraction and molecular simulations. We observed that, in DCM dogs, the amount of myosin heads in the stabilizing conformational state also known as super-relaxed (SRX) is significantly increased when compared with NF dogs. We also found that myosin heads are blocked in this SRX state preventing a proper length dependent activation, subsequently hindering myosin head recruitment and force-generating capacity. Despite these, our data also demonstrate that when applying EMD-57033, a small molecule activating myosin, SRX-related detrimental effects can be rescued. Taken together, our results suggest that myosin SRX contributes to the DCM pathophysiology and that the observed negative changes are reversible, giving hope for a myosin-centered pharmacological treatment of this particular cardiac disease.

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.

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