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The myosin super-relaxed state and human dilated cardiomyopathy

Award Number: F31HL170558
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 12/19/2025
AWARD TERMINATION DATE: 09/05/2026

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The myosin super-relaxed state and human dilated cardiomyopathy - Project Summary/Abstract Dilated cardiomyopathies are a frequent cause of heart failure worldwide, characterized by reduced systolic function and left ventricular dilation. Dilated cardiomyopathy has been linked to various causes, including viral infections, drug abuse, endocrine dysfunction, and genetic mutations. Reduced effective myocardial contractility presents as a symptom early in disease progression of dilated cardiomyopathy. Studying the molecular basis of decreased contractility by investigating the myosin motors that power contractions can provide important insight and allow testing of potential therapeutic modulation. Current therapeutics for dilated cardiomyopathy (e.g., ACE inhibitors, β-blockers, etc.) target symptoms but do not attenuate the underlying source of contractile dysfunction. At the molecular level, force generation in cardiac muscle is determined by the number of myosin motors that bind to the actin thin-filament during the systolic rise of calcium. Once myosin motors bind, myosins hydrolyze ATP and undergo conformational steps to generate force. Recent attention has focused on the myosin biochemical super-relaxed state, an energy-conserving, auto-inhibited state of cardiac myosin that determines the proportion of myosin motors available. Thus, the amount of myosin motors in the super-relaxed state modulates the magnitude of myosin motors available to generate sarcomere power upon activation. The stability of the super-relaxed state can be modulated by phosphorylation of regulatory light chain and myosin binding protein C. Additionally, as force increases, stress on the thick filament rises resulting in the release of myosin heads, allowing greater force production. A decrease in available myosin motors as a result of a shift towards the super-relaxed state is a potential mechanism of systolic dysfunction in human dilated cardiomyopathy and has yet to be fully investigated. Therefore, our central hypothesis is that depressed contractile force in dilated cardiomyopathy results from increased myosins in the super-relaxed state (Aim 1) mediated by depressed regulatory protein phosphorylation (Aim 2), which may be able to be reversed with the use of myosin activators (Aim 3). To test our hypothesis, we will utilize the fluorescent ATP pulse-chase technique to quantify the proportion of myosins in the super-relaxed state and test the effects of myosin activators at short and long sarcomere lengths. Also, using Phos-TagTM western blotting, we will measure the phosphorylation status of regulatory proteins. This proposal will provide novel insight into the effects of myosin activators on the super-relaxed state, demonstrate fundamental aspects of myosin biochemical states, and their role in the molecular basis of human dilated cardiomyopathy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2027 ( Subtotal = -$3,794 )
2027	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	2	10/27/2026	NON-COMPETING CONTINUATION	-$3,794
														Subtotal = -$3,794

Issue Date FY: 2026 ( Subtotal = -$11,567 )
2026	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	2	9/4/2026	TERMINATION	-$11,567
														Subtotal = -$11,567

Issue Date FY: 2025 ( Subtotal = $35,886 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	001	2	6/23/2025	NON-COMPETING CONTINUATION	$564
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	2	4/9/2025	NON-COMPETING CONTINUATION	$35,322
														Subtotal = $35,886

Issue Date FY: 2024 ( Subtotal = $35,322 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	002	1	9/6/2024	NEW	$1,280
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	001	1	3/1/2024	NEW	$0
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	1	3/1/2024	NEW	$34,042
														Subtotal = $35,322

Grand Total All Awards = $55,847

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The myosin super-relaxed state and human dilated cardiomyopathy

Award Number: F31HL170558

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 12/19/2025

AWARD TERMINATION DATE: 09/05/2026

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