Slow skeletal myosin binding protein C, encoded by MYBPC1, is a key sarcomeric protein that regulates muscle contractility. While MYBPC1 variants are typically associated with distal arthrogryposis, recently, novel variants have also been associated with myogenic tremors. Here, we examined the functional consequences of the novel MYBPC1:p.G132R variant in isolated human slow- and fast-twitch myofibers to determine whether the clinically observed tremors arise from sarcomeric dysfunction. We also evaluated mavacamten, a slow-myosin inhibitor, as a potential therapeutic approach to reduce the observed myogenic tremors.
In biref, permeabilized patient myofibers activated across increasing calcium concentrations presented with marked weakness, reflected by reduced maximal tension, however, without changes in calcium sensitivity. During activation, both myofiber types displayed spontaneous oscillatory contractions (SPOCs), most frequent at pCa 6.2, which correspondes to a sub-maximal muscle activation. SPOC amplitude and frequency varied with sarcomere length, temperature, and fiber type and from a mechanistic point of view, we showed that the G132R variant shifted the equilibrium of the myosin head conformational states toward the disordered-relaxed state.
Therapeutically, mavacamten which is know to stabilize the myosin in the super-relaxed state significantly reduced the SPOC amplitude and frequency in treated human myofibers.
Overall, our findings indicate that muscle weakness and tremors in patients carrying the MYBPC1:p.G132R variant originate from sarcomeric dysfunction. The marked improvement with mavacamten highlights the promise of myosin-targeted modulators for treating myogenic tremors. Further reserach into the molecular basis of SPOCs and contractile impairment may guide the development of future therapies not only for MYBPC1 variants, but also variants in other sarcomeric genes that are associated with tremor.