# Genetics and Molecular Biology of Striated Muscle Myosin

> **NIH NIH R37** · SAN DIEGO STATE UNIVERSITY · 2021 · $515,469

## Abstract

PROJECT SUMMARY
This application probes the role of the myosin motor protein in aging and in progressive, genetically based
diseases of skeletal and cardiac muscles. We will employ a multidisciplinary approach that takes advantage of
the powerful genetic tools available for Drosophila melanogaster along with a broad range of expertise that
allows us to study myosin in an integrative manner, from its crystal structure and biochemical function through
its effects upon muscle ultrastructure, fiber mechanical properties, cardiac physiology and locomotion. For Aim
1, we will examine the functional significance of specific residues within the skeletal muscle myosin motor and
rod domains that are post-translationally modified during human aging. Using transgenic Drosophila, we will
assess the effects of mutations at these sites on myosin ATPase activity, in vitro motility, thick filament
formation and stability, indirect flight and jump muscle ultrastructure, fiber mechanics and organism
locomotion. We will test the hypothesis that specific myosin amino acid residues that are subject to age-related
post-translational modifications are critical for myosin's biochemical properties and structure and function of the
myofibrillar apparatus. For Aim 2, we will examine how amino acid mutations associated with human age-
related dilated cardiomyopathy affect the structure and biochemical properties of the myosin molecule, as well
as the structure and physiological function of the Drosophila heart. We will gain mechanistic insights into
protein structural features that are vital for cardiac myosin function using a unique in vivo method to produce
mutant forms of the myosin protein for crystallography. Further, we will assess the power of the Drosophila
system as a screening tool for identifying putative dilated cardiomyopathy myosin alleles defined in humans.
This combined protein structural and in vivo screening approach will test the hypothesis that mutations that
cause human dilated cardiomyopathy disrupt intramolecular communication leading to depressed myosin
motor function, Drosophila cardiac dilation, heart wall thinning and reduced cardiac output. For Aim 3, we will
define the roles of specific chaperone-affiliated proteins in inclusion body myopathy type 3, a progressive
skeletal muscle disorder. Specific small heat shock proteins, a mitochondrial chaperone and an ubiquitin ligase
anomalously accumulate in aggregates in our Drosophila model of this disease. Up- or down-regulating their
expression, followed by structural and functional analyses of skeletal muscles, will yield insights into their roles
in aging and in degenerative muscle disease. We will test the hypothesis that manipulating the levels of
specific small heat shock proteins, a mitochondrial chaperone and an ubiquitin ligase can ameliorate or
exacerbate progressive myosin-based myopathy phenotypes. Overall, our project will take advantage of an
innovative experimental system to test signifi...

## Key facts

- **NIH application ID:** 10135975
- **Project number:** 5R37GM032443-36
- **Recipient organization:** SAN DIEGO STATE UNIVERSITY
- **Principal Investigator:** Sanford I Bernstein
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $515,469
- **Award type:** 5
- **Project period:** 1983-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135975

## Citation

> US National Institutes of Health, RePORTER application 10135975, Genetics and Molecular Biology of Striated Muscle Myosin (5R37GM032443-36). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10135975. Licensed CC0.

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