Abstract
Myosinopathies are defined as a group of muscle disorders characterized by mutations in genes encoding myosin heavy chains. Their exact molecular and cellular mechanisms remain unclear. In the present study, we have focused our attention on a MYH1-related E321G amino acid substitution within the head region of the type IIx skeletal myosin heavy chain, associated with clinical signs of atrophy, inflammation and/or profound rhabdomyolysis, known as equine myosin heavy chain myopathy. We performed Mant-ATP chase experiments together with force measurements on isolated IIx myofibres from control horses (MYH1E321G−/−) and Quarter Horses homozygous (MYH1E321G+/+) or heterozygous (MYH1E321G+/−) for the E321G mutation. The single residue replacement did not affect the relaxed conformations of myosin molecules. Nevertheless, it significantly increased its active behaviour as proven by the higher maximal force production and Ca2+ sensitivity for MYH1E321G+/+ in comparison with MYH1E321G+/− and MYH1E321G−/− horses. Altogether, these findings indicate that, in the presence of the E321G mutation, a molecular and cellular hyper-contractile phenotype occurs which could contribute to the development of the myosin heavy chain myopathy.
Highlights
Myosinopathies are a heterogeneous group of congenital myopathies clinically ranging from late onset mild muscle dysfunction to early lethal symptomatic manifestations [1,2].They are associated with mutations in the MYH3, MYH8, MYH7, MYH2, MYH1 and MYH4 genes, all encoding for myosin heavy chain isoforms present in the foetus, neonatal and/or adult skeletal muscles [1,2]
In Quarter Horses, the most popular breed in the USA with over 4 million horses registered by the American Quarter Horse Association, a pathogenic co-dominant mutation in the MYH1 gene encoding for the fast skeletal myosin heavy chain type IIx (MYH1E321G ) has been identified in the motor domain and linked to a detrimental inflammatory myopathy known as equine immune-mediated myositis [8–10]
All the results presented below focused on myofibres expressing the fast skeletal myosin heavy chain type IIx where the subtle amino acid substitution occurs
Summary
Myosinopathies are a heterogeneous group of congenital myopathies clinically ranging from late onset mild muscle dysfunction to early lethal symptomatic manifestations [1,2]. They are associated with mutations in the MYH3, MYH8, MYH7, MYH2, MYH1 and MYH4 genes, all encoding for myosin heavy chain isoforms present in the foetus, neonatal and/or adult skeletal muscles [1,2]. Despite this knowledge and despite the fact that we know that more than 90% are missense mutations, resulting in the replacement of just one residue in the head domain, converter or tail regions of the myosin molecule [3–6], the exact pathophysiological mechanisms remain unclear. In Quarter Horses, the most popular breed in the USA with over 4 million horses registered by the American Quarter Horse Association, a pathogenic co-dominant mutation in the MYH1 gene encoding for the fast skeletal myosin heavy chain type IIx (MYH1E321G ) has been identified in the motor domain and linked to a detrimental inflammatory myopathy known as equine immune-mediated myositis [8–10]
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