Search

Abstract: Ca2+ ions are key regulators of skeletal muscle contraction. By binding to contractile proteins, they initiate a cascade of molecular events leading to cross-bridge formation and ultimately, muscle shortening and force production. The ability of contractile proteins to respond to Ca2+ attachment, also known as Ca2+ sensitivity, is often compromised in acquired and congenital skeletal muscle disorders. It constitutes, undoubtedly, a major physiological cause of weakness for patients. In this review, we discuss recent studies giving strong molecular and cellular evidence that pharmacological modulators of some of the contractile proteins, also termed Ca2+ sensitizers, are efficient agents to improve Ca2+ sensitivity and function in diseased skeletal muscle cells. In fact, they compensate for the impaired contractile proteins response to Ca2+ binding. Currently, such Ca2+ sensitizing compounds are successfully used for reducing problems in cardiac disorders. Therefore, in the future, under certain conditions, these agents may represent an emerging class of agents to enhance the quality of life of patients suffering from skeletal muscle weakness. [Copyright &y& Elsevier]

X-linked myotubular myopathy (XL-MTM) is a rare and often lethal congenital myopathy, clinically characterized by muscle weakness. Its underlying molecular mechanisms remain incompletely understood. As myosin has been implicated in the pathophysiology of other forms of congenital myopathies, in the present study, we aimed to define whether muscle myosin is dysfunctional in the context of XL-MTM. For that, we used muscle tissue from human patients and a canine model. We isolated individual muscle fibres from these two species and performed loaded Mant-ATP chase experiments. Our preliminary results indicate a shift of myosin metabolic/biochemical states towards highly energy-consuming conformations in human and canine XL-MTM. Subsequently, to reverse this alteration potentially contributing to muscle fatigue, we investigated the effects of an ATP-conserving drug targeting myosin, mavacamten, using a well-defined mouse model of XL-MTM lacking myotubularin. The results are currently being analysed and include histology as well as untargeted global proteomics. Potentially, taken together, these data will lead to a better understanding of XL-MTM and the potency of myosin as a drug target. [ABSTRACT FROM AUTHOR]

In skeletal muscle, troponin T (TnT) exists in two isoforms, slow skeletal TnT (ssTnT) and fast skeletal TnT (fsTnT), encoded by the TNNT1 and TNNT3 genes, respectively. Nonsense or missense TNNT1 mutations have been identified and associated with skeletal muscle weakness, fatigue and a condition named Nemaline Myopathy. Little is known about the underlying mechanisms by which these TNNT1 mutations ultimately lead to muscle dysfunction, preventing the development of appropriate therapeutic interventions. Here, we aimed to identify the molecular biochemical and biophysical mechanisms. For that, we isolated skeletal myofibres from Nemaline patients with known TNNT1 mutations as well as from age- and gender-matched controls. We then performed a combination of structural and functional assays. Besides the mutations, our studies revealed unusual ssTnT and fsTnT expressions and post-translational modifications (PTM). We also observed that, in the presence of TNNT1 mutations and aberrant PTMs, the relaxed thin filament was more compliant and extensible, mimicking the contraction state. This was accompanied by the production of higher forces at low calcium concentrations. Taken together, our findings highlight a potential TnT remodelling ultimately leading to molecular hyper-contractility. This then suggests the use of myosin/contractile inhibitors for the treatment of Nemaline Myopathy due to TNNT1 mutations. [ABSTRACT FROM AUTHOR]