Prolonged cross-bridge binding triggers muscle dysfunction in a Drosophila model of myosin-based hypertrophic cardiomyopathy

Kronert, William A.; Bell, Kaylyn M.; Viswanathan, Meera; Melkani, Girish C.; Trujillo, Adriana S.; Huang, Alice H.; Melkani, Anju; Cammarato, Anthony; Swank, Douglas M.; Bernstein, Sanford I.

doi:10.7554/elife.38064

Cited by 29 publications

(43 citation statements)

References 75 publications

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“…HCM is frequently characterized by altered Ca 2+ handling and elevated diastolic Ca 2+ levels, which promote actomyosin associations and impair relaxation. To determine the mechanism of restricted cardiac diameters and to rule out a potential contribution from disrupted Ca 2+ homeostasis, we incubated beating Hand > Act57B WT and Hand > Act57B M305L hearts in a solution containing 10 mM EGTA and 100 µM EGTA,AM 31,39 . EGTA-EGTA,AM chelates both extra-and intracellular Ca 2+ and arrests contraction.…”

Section: Resultsmentioning

confidence: 99%

A role for actin flexibility in thin filament-mediated contractile regulation and myopathy

et al. 2020

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Striated muscle contraction is regulated by the translocation of troponin-tropomyosin strands over the thin filament surface. Relaxation relies partly on highly-favorable, conformationdependent electrostatic contacts between actin and tropomyosin, which position tropomyosin such that it impedes actomyosin associations. Impaired relaxation and hypercontractile properties are hallmarks of various muscle disorders. The α-cardiac actin M305L hypertrophic cardiomyopathy-causing mutation lies near residues that help confine tropomyosin to an inhibitory position along thin filaments. Here, we investigate M305L actin in vivo, in vitro, and in silico to resolve emergent pathological properties and disease mechanisms. Our data suggest the mutation reduces actin flexibility and distorts the actin-tropomyosin electrostatic energy landscape that, in muscle, result in aberrant contractile inhibition and excessive force. Thus, actin flexibility may be required to establish and maintain interfacial contacts with tropomyosin as well as facilitate its movement over distinct actin surface features and is, therefore, likely necessary for proper regulation of contraction.

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Section: Resultsmentioning

confidence: 99%

A role for actin flexibility in thin filament-mediated contractile regulation and myopathy

et al. 2020

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“…In agreement with these observations, we have previously found, using our Drosophila model, that the HCM mutation R146N increased IFM contractility (Kronert et al . ). Interestingly, the mutations characterized in these studies (that lead to increased contractility) have been frequently associated with more severe clinical symptoms compared to the R249Q mutation (Tyska et al .…”

Section: Discussionmentioning

confidence: 97%

The R249Q hypertrophic cardiomyopathy myosin mutation decreases contractility in Drosophila by impeding force production

Bell

Kronert

Huang

et al. 2019

The Journal of Physiology

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Key pointsr Hypertrophic cardiomyopathy (HCM) is a genetic disease that causes thickening of the heart's ventricular walls and is a leading cause of sudden cardiac death. r HCM is caused by missense mutations in muscle proteins including myosin, but how these mutations alter muscle mechanical performance in largely unknown.r We investigated the disease mechanism for HCM myosin mutation R249Q by expressing it in the indirect flight muscle of Drosophila melanogaster and measuring alterations to muscle and flight performance.r Muscle mechanical analysis revealed R249Q decreased muscle power production due to slower muscle kinetics and decreased force production; force production was reduced because fewer mutant myosin cross-bridges were bound simultaneously to actin.r This work does not support the commonly proposed hypothesis that myosin HCM mutations increase muscle contractility, or causes a gain in function; instead, it suggests that for some myosin HCM mutations, hypertrophy is a compensation for decreased contractility.Abstract Hypertrophic cardiomyopathy (HCM) is an inherited disease that causes thickening of the heart's ventricular walls. A generally accepted hypothesis for this phenotype is that myosin heavy chain HCM mutations increase muscle contractility. To test this hypothesis, we expressed an HCM myosin mutation, R249Q, in Drosophila indirect flight muscle (IFM) and assessed myofibril structure, skinned fibre mechanical properties, and flight ability. Mechanics experiments were performed on fibres dissected from 2-h-old adult flies, prior to degradation of IFM myofilament structure, which started at 2 days old and increased with age. Homozygous and heterozygous R249Q fibres showed decreased maximum power generation by 67% and 44%, respectively. Kaylyn Bell received her Bachelor's Degree in Biochemistry and Biophysics at Rensselaer Polytechnic Institute. She is continuing her research in biophysics at RPI with Dr. Douglas Swank for her PhD. Her work uses the Drosophila model system to characterize the muscle mechanical properties of myosin mutations that cause the heart disease hypertrophic cardiomyopathy, and the skeletal muscle disease Freeman-Sheldon Syndrome. She is also investigating a possible myosin based mechanism behind the muscle phenomenon known as stretch activation. K. M. Bell and W. A. Kronert contributed equally to this work. J Physiol 597.9 Decreases in force and work and slower overall muscle kinetics caused homozygous fibres to produce less power. While heterozygous fibres showed no overall slowing of muscle kinetics, active force and work production dropped by 68% and 47%, respectively, which hindered power production. The muscle apparent rate constant 2πb decreased 33% for homozygous but increased for heterozygous fibres. The apparent rate constant 2πc was greater for homozygous fibres. This indicates that R249Q myosin is slowing attachment while speeding up detachment from actin, resulting in less time bound. Decreased IFM power output caused 43% and 33% decreases in Drosophila ...

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“…Hence, the ATP demand of these muscle fibers during flight is extremely high. With its strict aerobic metabolism and its stretch activation mechanism requiring high mechanical tension, insect flight muscles biomechanically and energetically resemble the mammalian heart muscle 14,15 .…”

Section: To Investigate the Interplay Between Myofibrils And Mitochonmentioning

confidence: 99%

Myofibril and mitochondria morphogenesis are coordinated by a mechanical feedback mechanism in muscle

Avellaneda

Rodier

Daian

et al. 2020

Preprint

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Complex animals build specialised muscle to match specific biomechanical and energetic needs. Hence, composition and architecture of sarcomeres as well as mitochondria are muscle type specific. However, mechanisms coordinating mitochondria with sarcomere morphogenesis are elusive. Here we use Drosophila muscles to demonstrate that myofibril and mitochondria morphogenesis are intimately linked. In flight muscles, the muscle selector spalt instructs mitochondria to intercalate between myofibrils, which in turn mechanically constrain mitochondria into elongated shapes. Conversely in cross-striated muscles, mitochondria networks surround myofibril bundles, contacting myofibrils only with thin extensions. To investigate the mechanism causing these differences, we manipulated mitochondrial dynamics and found that increased mitochondrial fusion during myofibril assembly prevents mitochondrial intercalation in flight muscles. Strikingly, this coincides with the expression of cross-striated muscle specific sarcomeric proteins. Consequently, flight muscle myofibrils convert towards a partially cross-striated architecture. Together, these data suggest a biomechanical feedback mechanism downstream of spalt synchronizing mitochondria with myofibril morphogenesis.

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Prolonged cross-bridge binding triggers muscle dysfunction in a Drosophila model of myosin-based hypertrophic cardiomyopathy

Cited by 29 publications

References 75 publications

A role for actin flexibility in thin filament-mediated contractile regulation and myopathy

A role for actin flexibility in thin filament-mediated contractile regulation and myopathy

The R249Q hypertrophic cardiomyopathy myosin mutation decreases contractility in Drosophila by impeding force production

Myofibril and mitochondria morphogenesis are coordinated by a mechanical feedback mechanism in muscle

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