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Sarcomeric deficits underlie MYBPC1-associated myopathy with myogenic tremor
Janelle Geist Hauserman, … , Christopher Ward, Aikaterini Kontrogianni-Konstantopoulos
Janelle Geist Hauserman, … , Christopher Ward, Aikaterini Kontrogianni-Konstantopoulos
Published August 26, 2021
Citation Information: JCI Insight. 2021;6(19):e147612. https://doi.org/10.1172/jci.insight.147612.
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Research Article Cell biology Muscle biology

Sarcomeric deficits underlie MYBPC1-associated myopathy with myogenic tremor

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Abstract

Myosin binding protein-C slow (sMyBP-C) comprises a subfamily of cytoskeletal proteins encoded by MYBPC1 that is expressed in skeletal muscles where it contributes to myosin thick filament stabilization and actomyosin cross-bridge regulation. Recently, our group described the causal association of dominant missense pathogenic variants in MYBPC1 with an early-onset myopathy characterized by generalized muscle weakness, hypotonia, dysmorphia, skeletal deformities, and myogenic tremor, occurring in the absence of neuropathy. To mechanistically interrogate the etiologies of this MYBPC1-associated myopathy in vivo, we generated a knock-in mouse model carrying the E248K pathogenic variant. Using a battery of phenotypic, behavioral, and physiological measurements spanning neonatal to young adult life, we found that heterozygous E248K mice faithfully recapitulated the onset and progression of generalized myopathy, tremor occurrence, and skeletal deformities seen in human carriers. Moreover, using a combination of biochemical, ultrastructural, and contractile assessments at the level of the tissue, cell, and myofilaments, we show that the loss-of-function phenotype observed in mutant muscles is primarily driven by disordered and misaligned sarcomeres containing fragmented and out-of-register internal membranes that result in reduced force production and tremor initiation. Collectively, our findings provide mechanistic insights underscoring the E248K-disease pathogenesis and offer a relevant preclinical model for therapeutic discovery.

Authors

Janelle Geist Hauserman, Janis Stavusis, Humberto C. Joca, Joel C. Robinett, Laurin Hanft, Jack Vandermeulen, Runchen Zhao, Joseph P. Stains, Konstantinos Konstantopoulos, Kerry S. McDonald, Christopher Ward, Aikaterini Kontrogianni-Konstantopoulos

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Figure 1

Generation and physiological characterization of the MYBPC1 E248K KI mouse model.

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Generation and physiological characterization of the MYBPC1 E248K KI mou...
(A) Schematic representation of the sMyBP-C domain structure and location of the E248K variant in the M-motif; white and gray ovals denote immunoglobulin and fibronectin-III domains, dark gray and light gray horizontal rectangles indicate the Pro/Ala and M-motif, and colored rectangles depict spliced sequences. (B) Approximately 15% of heterozygous KI mice failed to survive through weaning but showed similar survival trends as WT past 3 weeks of age; survival chart: n = 295 WT (151 male and 144 female) and n = 154 heterozygous KI (80 male and 74 female). The overall survival bar-graph shows: n = 97 WT (52 male and 45 female) and n = 65 heterozygous KI (37 male and 28 female). (C) Both male and female heterozygous KI mice were significantly smaller compared with WT littermates through 24 weeks of age; n = 22 WT (10 male and 12 female) and n = 24 heterozygous KI (13 male and 11 female). (D) During the first 15 days of postnatal life, average tremor value at rest was significantly higher in heterozygous KI pups compared with WT; n = 14 WT (4 male and 10 female) and n = 9 heterozygous KI (6 male and 3 female). (E) Heterozygous KI pups needed significantly longer time to right than WT at P6; n = 27 WT and n = 16 heterozygous KI. (F) High-frequency tremor was identified in 92% (12 of 13) of heterozygous KI mice at 4 weeks compared with 10% (1 of 10) of WT using a custom-designed vibration plate. Representative tremor frequency traces are shown, indicating random movement in WT and bursts of tremor in heterozygous KI animals; areas marked with red dashed boxes are blown up for comparison and detailed evaluation; n = 10 WT (6 male and 4 female) and n = 13 heterozygous KI (6 male and 7 female). Statistical significance was calculated with a 2-tailed Student’s t test for all applicable assays. #P < 0.05, *P < 0.01.

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