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Defining Molecular Structure and Dynamics of the Skeletal Muscle Myosin Super Relaxed State: One Molecule at a Time

Award Number: R21AR088256
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/17/2026
PERIOD OF PERFORMANCE END DATE: 09/30/2028

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Defining Molecular Structure and Dynamics of the Skeletal Muscle Myosin Super Relaxed State: One Molecule at a Time - The myosin super-relaxed (SRX) state is an autoinhibited, energy conserving state that many consider a reserve myosin “pool” that can be recruited upon physiological demand and thus is critical for regulation of muscle energetics and contractility. Despite its importance, the field lacks consensus on whether the SRX enzymatic state is structurally defined by the Interacting Heads Motif (IHM), a folded configuration of the myosin heads. Are the SRX and IHM states inextricably linked or dynamically independent? Do SRX myosin molecules remain stable for prolonged periods of time or readily exchange with the uninhibited “Disordered Relaxed” or DRX state that can attach to the actin thin filament and generate force? How are these states regulated through interactions with neighboring myosin, regulatory proteins such as MyBP-C, or mechanical forces within the sarcomere, muscle’s most basic contractile unit? These questions are central to understanding muscle function and have profound implications for developing therapeutics to address pathologies where SRX dysregulation is implicated such as familial myopathies and more acute conditions such as ventilator-induced diaphragm dysfunction. Utilizing single molecule techniques with high spatial and temporal resolution, we propose an innovative combination of single-molecule ATP turnover assays with Forster Resonance Energy Transfer (FRET) measurements to simultaneously observe both the enzymatic and structural states of individual myosin molecules isolated from rat soleus muscle. This dual readout surpasses traditional bulk assays and static imaging, as it enables dynamic tracking of myosin structure and function across multiple ATPase cycles and even during a single hydrolysis event (Aim 1). We will then apply this combination of single molecule approaches to spatially map the SRX/IHM states within isolated native thick filaments to assess how myosin-binding protein C (MyBP-C) and neighboring myosin interactions within the thick filaments regulate SRX/IHM dynamics (Aim 2A) and finally to intact sarcomeres within a myofibril under mechanical load in the optical trap (Aim 2B), offering the first direct test of thick filament mechanosensing at the molecular level. By defining the dynamics and relationship between the SRX and IHM states, and how they are each regulated by protein interactions and mechanical forces, this research promises to redefine our understanding of muscle regulation and inform therapeutic strategies for SRX-related pathologies.


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: 2026 ( Subtotal = $358,806 )
2026	2026	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/17/2026	NEW	$358,806
														Subtotal = $358,806

Grand Total All Awards = $358,806

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Defining Molecular Structure and Dynamics of the Skeletal Muscle Myosin Super Relaxed State: One Molecule at a Time

Award Number: R21AR088256

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/17/2026

PERIOD OF PERFORMANCE END DATE: 09/30/2028

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