# Structural Dynamics of the Myosin Super Relaxed State in Aging Muscle and Metabolic Disease

> **NIH NIH F30** · UNIVERSITY OF MINNESOTA · 2021 · $22,388

## Abstract

Project Summary
The myosin super-relaxed (SRX) state, first described six years ago, is emerging as an important player in
muscle regulation and function, yet its mechanistic structure and dynamics have not been resolved. The goal
of this proposal is to incorporate time-resolved fluorescence resonance energy transfer (TR-FRET) with
quantitative epifluorescence microscopy of fluorescent nucleotides, to detect and quantitate the SRX in
chemically skinned skeletal muscle fibers from different disease mouse models. The long-term goal is to
establish the role of SRX in age-related attenuation of muscle function, and use these insights to design
therapeutic approaches. The population of SRX myosin in resting skeletal muscle is as much as 50%. These
molecules are sequestered on the myosin thick-filament backbone and are thus auto-inhibited, catalyzing ATP
hydrolysis about 10 times slower than purified myosin in solution, while generating no force. My proposal
focuses on the role of SRX in the attenuation of muscle function with age, focusing on three independent but
inter-related Aims: concerning the roles of sex-specificity (Aim 1), muscle thermogenesis and thus control of
whole body basal metabolic rate (Aim 2), and metabolic diseases such as obesity and diabetes (Aim 3). Thus,
the myosin SRX provides a platform for potential innovative treatments for obesity and diabetes. However, the
molecular mechanism by which this SRX state affects aging muscle physiology and pathophysiology is
unresolved. To solve this problem, my effort will be focused on applying site-directed spectroscopic probes on
myosin to elucidate its structural changes as it undergoes transitions between the super-relaxed state and the
normal relaxed state. The SRX can be rapidly mobilized into the normal relaxed or the active state in response
to regulatory allosteric cues such as increased in cellular calcium, regulatory light chain (RLC) phosphorylation,
and decreased temperature. These perturbations will be thoroughly tested on each proposed mouse model
(Aims 1-3). This will be the first time that the molecular dynamics of SRX myosin will be directly studied
through the physiological lens of aging and its associated metabolic disorders. Results from this work will
provide crucial insights into the nature of the aging process on skeletal myosin and map a path toward novel
therapies to treat diseases and extend healthy, active years of life by targeting myosin. The present fellowship
proposal will also provide extensive training opportunity in muscle biochemistry, biophysics, and physiology,
contributing to a meaningful MD/PhD degree. The training will prepare me to become an independent
biomedical researcher with the means to apply optical spectroscopy to translational science, to both appreciate
the molecular basis of disease and subsequent development of new treatments. This work aligns strongly with
the mission statement of the NIA, by increasing the molecular understanding of the...

## Key facts

- **NIH application ID:** 10223178
- **Project number:** 5F30AG057108-05
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Lien Ai Phung
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $22,388
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223178

## Citation

> US National Institutes of Health, RePORTER application 10223178, Structural Dynamics of the Myosin Super Relaxed State in Aging Muscle and Metabolic Disease (5F30AG057108-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10223178. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*