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https://observatorio.fm.usp.br/handle/OPI/57449
Title: | Abnormal myosin post-translational modifications and ATP turnover time associated with human congenital myopathy-related <i>RYR1</i> mutations |
Authors: | SONNE, Alexander; ANTONOVIC, Anna Katarina; MELHEDEGAARD, Elise; AKTER, Fariha; ANDERSEN, Jesper L.; JUNGBLUTH, Heinz; WITTING, Nanna; VISSING, John; ZANOTELI, Edmar; FORNILI, Arianna; OCHALA, Julien |
Citation: | ACTA PHYSIOLOGICA, v.239, n.2, 2023 |
Abstract: | AimConditions related to mutations in the gene encoding the skeletal muscle ryanodine receptor 1 (RYR1) are genetic muscle disorders and include congenital myopathies with permanent weakness, as well as episodic phenotypes such as rhabdomyolysis/myalgia. Although RYR1 dysfunction is the primary mechanism in RYR1-related disorders, other downstream pathogenic events are less well understood and may include a secondary remodeling of major contractile proteins. Hence, in the present study, we aimed to investigate whether congenital myopathy-related RYR1 mutations alter the regulation of the most abundant contractile protein, myosin. MethodsWe used skeletal muscle tissues from five patients with RYR1-related congenital myopathy and compared those with five controls and five patients with RYR1-related rhabdomyolysis/myalgia. We then defined post-translational modifications on myosin heavy chains (MyHCs) using LC/MS. In parallel, we determined myosin relaxed states using Mant-ATP chase experiments and performed molecular dynamics (MD) simulations. ResultsLC/MS revealed two additional phosphorylations (Thr1309-P and Ser1362-P) and one acetylation (Lys1410-Ac) on the & beta;/slow MyHC of patients with congenital myopathy. This method also identified six acetylations that were lacking on MyHC type IIa of these patients (Lys35-Ac, Lys663-Ac, Lys763-Ac, Lys1171-Ac, Lys1360-Ac, and Lys1733-Ac). MD simulations suggest that modifying myosin Ser1362 impacts the protein structure and dynamics. Finally, Mant-ATP chase experiments showed a faster ATP turnover time of myosin heads in the disordered-relaxed conformation. ConclusionsAltogether, our results suggest that RYR1 mutations have secondary negative consequences on myosin structure and function, likely contributing to the congenital myopathic phenotype. |
Appears in Collections: | Artigos e Materiais de Revistas Científicas - FM/MNE Artigos e Materiais de Revistas Científicas - HC/ICHC Artigos e Materiais de Revistas Científicas - LIM/15 Artigos e Materiais de Revistas Científicas - LIM/45 |
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