# Redefining The Role Of Myosin Essential Light Chain In Cardiac Muscle

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $383,750

## Abstract

ABSTRACT
The scientific premise of this application regards the cardiac specific expression of the long ELC containing
the N-terminal ELC extension (N-ELC) and its physiologically important role in regulating myosin motor function
and force production in muscle. We hypothesize that cardiac N-ELC works as a molecular linker and/or
energetic switch of the actin-myosin interaction by regulating the transition of myosin cross-bridges from a super-
relaxed (SRX) to a disordered-relaxed (DRX) state, and the proportion of myosin heads that are available for the
interaction with actin. In DRX, the myosin heads protrude into the interfilament space but are restricted from
binding to actin, while in the SRX state, the heads are neatly ordered along the thick filament axis but cycle at a
highly inhibited ATP turnover rate. We further hypothesize that hypertrophic cardiomyopathy mutations in
myosin ELC promote the SRX-to-DRX transition and the deletion of the N-ELC counteracts this transition and
stabilizes the energy conservation SRX state. We will test these hypotheses using two mouse models of
hypertrophic HCM-A57G (Alanine57Glycine) and restrictive RCM-E143K (Glutamate143Lysine)
cardiomyopathy. We will also use transgenic Δ43 mice expressing a 43-aa truncated ELC, and double transgenic
mice: A57GxΔ43 and E143KxΔ43, expressing Δ43-ELC in the background of HCM or RCM mutations. The data
will be compared to age and sex matched WT-ELC mice expressing the human ventricular ELC (MYL3 gene).
SPECIFIC AIM 1: DEFINE THE ROLE OF MYOSIN ELC AND ITS N-TERMINUS (N-ELC) IN THE REGULATION
OF MYOSIN MOTOR FUNCTION AND CARDIAC MUSCLE CONTRACTION. This aim will focus on the molecular
triggers of ELC-induced heart remodeling studied at the level of myosin molecules, myofibers and the whole
heart. The N-ELC-dependent regulation of actin-myosin interactions will be studied using: 1) mant-ATP-chase
assays and the proportion of myosin heads in SRX vs. DRX states; 2) Quantum dot-labeled actin±Tm-Tn motility
assays; 3) Skinned and intact muscle fibers and force-pCa as well as force and calcium transient measurements;
and 4) echocardiography and invasive hemodynamics to assess contractile responses of the heart in vivo.
SPECIFIC AIM 2: THE ROLE MYOSIN ELC IN ENERGETIC REMODELING OF THE HEART IN MOUSE MODELS
OF CARDIOMYOPATHY. The analysis of the metabolic landscape in A57G, E143K, Δ43, A57GxΔ43 and
E143KxΔ43 vs. WT hearts will be performed to identify the specific mechanisms that govern energy utilization
in all ELC-mutant vs. WT mice. Mitochondrial function will be assessed by determination of mitochondrial
respiration, enzymatic activity of respiratory complexes as well as ATP production/consumption. Steady-state
levels of candidate proteins implicated in energy production such as Hexokinases I and II, various mitochondrial
respiratory chain subunits (Complexes I to V) as well as peroxisome proliferator-activated receptor coactivator α
(PGC-1α) will be assessed in all models ...

## Key facts

- **NIH application ID:** 9971648
- **Project number:** 1R01HL143830-01A1
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Danuta Szczesna-Cordary
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,750
- **Award type:** 1
- **Project period:** 2020-04-05 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971648

## Citation

> US National Institutes of Health, RePORTER application 9971648, Redefining The Role Of Myosin Essential Light Chain In Cardiac Muscle (1R01HL143830-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9971648. Licensed CC0.

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