TY - JOUR

T1 - Human skeletal myopathy myosin mutations disrupt myosin head sequestration

AU - Carrington, Glenn

AU - Hau, Abbi

AU - Kosta, Sarah

AU - Dugdale, Hannah F.

AU - Muntoni, Francesco

AU - D’Amico, Adele

AU - Van den Bergh, Peter

AU - Romero, Norma B.

AU - Malfatti, Edoardo

AU - Vilchez, Juan Jesus

AU - Oldfors, Anders

AU - Pajusalu, Sander

AU - Õunap, Katrin

AU - Giralt-Pujol, Marta

AU - Zanoteli, Edmar

AU - Campbell, Kenneth S.

AU - Iwamoto, Hiroyuki

AU - Peckham, Michelle

AU - Ochala, Julien

N1 - Publisher Copyright: © 2023, Carrington et al.

PY - 2023

Y1 - 2023

N2 - Myosin heavy chains encoded by MYH7 and MYH2 are abundant in human skeletal muscle and important for muscle contraction. However, it is unclear how mutations in these genes disrupt myosin structure and function leading to skeletal muscle myopathies termed myosinopathies. Here, we used multiple approaches to analyze the effects of common MYH7 and MYH2 mutations in the light meromyosin (LMM) region of myosin. Analyses of expressed and purified MYH7 and MYH2 LMM mutant proteins combined with in silico modeling showed that myosin coiled coil structure and packing of filaments in vitro are commonly disrupted. Using muscle biopsies from patients and fluorescent ATP analog chase protocols to estimate the proportion of myosin heads that were super-relaxed, together with x-ray diffraction measurements to estimate myosin head order, we found that basal myosin ATP consumption was increased and the myosin super-relaxed state was decreased in vivo. In addition, myofiber mechanics experiments to investigate contractile function showed that myofiber contractility was not affected. These findings indicate that the structural remodeling associated with LMM mutations induces a pathogenic state in which formation of shutdown heads is impaired, thus increasing myosin head ATP demand in the filaments, rather than affecting contractility. These key findings will help design future therapies for myosinopathies.

AB - Myosin heavy chains encoded by MYH7 and MYH2 are abundant in human skeletal muscle and important for muscle contraction. However, it is unclear how mutations in these genes disrupt myosin structure and function leading to skeletal muscle myopathies termed myosinopathies. Here, we used multiple approaches to analyze the effects of common MYH7 and MYH2 mutations in the light meromyosin (LMM) region of myosin. Analyses of expressed and purified MYH7 and MYH2 LMM mutant proteins combined with in silico modeling showed that myosin coiled coil structure and packing of filaments in vitro are commonly disrupted. Using muscle biopsies from patients and fluorescent ATP analog chase protocols to estimate the proportion of myosin heads that were super-relaxed, together with x-ray diffraction measurements to estimate myosin head order, we found that basal myosin ATP consumption was increased and the myosin super-relaxed state was decreased in vivo. In addition, myofiber mechanics experiments to investigate contractile function showed that myofiber contractility was not affected. These findings indicate that the structural remodeling associated with LMM mutations induces a pathogenic state in which formation of shutdown heads is impaired, thus increasing myosin head ATP demand in the filaments, rather than affecting contractility. These key findings will help design future therapies for myosinopathies.

UR - http://www.scopus.com/inward/record.url?scp=85176217169&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.172322

DO - 10.1172/jci.insight.172322

M3 - Journal article

C2 - 37788100

AN - SCOPUS:85176217169

VL - 8

SP - 1

EP - 19

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 21

M1 - e172322

ER -