Abstract
Many mutations in the skeletal muscle α-actin gene (ACTA1) lead to muscle weakness and nemaline myopathy. Despite increasing clinical and scientific interest, the molecular and cellular pathogenesis of weakness remains unclear. Therefore, in the present study, we aimed at unraveling these mechanisms using muscles from a transgenic mouse model of nemaline myopathy expressing the ACTA1 Asp286Gly mutation. We recorded and analyzed the mechanics of membrane-permeabilized single muscle fibers. We also performed molecular energy state computations in the presence or absence of Asp286Gly. Results demonstrated that during contraction, the Asp286Gly acts as a “poison-protein” and according to the computational analysis it modifies the actin-actin interface. This phenomenon is likely to prevent proper myosin cross-bridge binding, limiting the fraction of actomyosin interactions in the strong binding state. At the cell level, this decreases the force-generating capacity, and, overall, induces muscle weakness. To counterbalance such negative events, future potential therapeutic strategies may focus on the inappropriate actin-actin interface or myosin binding.
Highlights
Nemaline myopathy (NM) is an under-appreciated congenital muscular disorder characterized clinically by skeletal muscle weakness and hypotonia; and pathologically by the presence of nemaline bodies within the muscle biopsy specimens [1]
We recently developed a transgenic mouse model that mimics NM caused by ACTA1 mutations [9]
The Tg(ACTA1)Asp286Gly mice carry a missense ACTA1 mutation that results in the substitution of one single amino acid in the actin protein (Asp286Gly in the mature protein, Asp288Gly according to the standard Human Genome Variation Society nomenclature) that was identified in a NM patient [9]
Summary
Nemaline myopathy (NM) is an under-appreciated congenital muscular disorder characterized clinically by skeletal muscle weakness and hypotonia; and pathologically by the presence of nemaline bodies within the muscle biopsy specimens [1]. NM has been shown to be caused by mutations in multiple different genes, including ACTA1 (encoding skeletal muscle a-actin) [2], NEB (nebulin) [3], TPM2 (b-tropomyosin) [4], TPM3 (a-tropomyosin) [5], TNNT1 (slow skeletal muscle troponin T) [6], CFL2 (muscle specific cofilin) [7] and KBTBD13 [8]. Despite this crucial knowledge, it remains unclear how most mutations disrupt muscle contractile function and lead to skeletal muscle weakness. To gain molecular insights into the dysfunction, we performed molecular energy computations in the presence or absence of Asp286Gly
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