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New mechanisms behind skeletal muscle endurance

Award Number: R01AR083916
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: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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New mechanisms behind skeletal muscle endurance - Stretch Activation (SA), a delayed force increase (FSA) following a rapid stretch, is known to be critical to the function of some muscle types, such as cardiac muscle, but its purpose in other types is not known. Even less is known about the mechanisms behind SA, limiting our ability to treat diseases involving SA loss. The few previous investigations of mammalian skeletal muscle suggested its FSA is too low to be important for function. However, our measurements of mouse slow-twitch muscle FSA at moderate and higher [Pi] contradict this interpretation, suggesting SA contributes at least 1/3 of total force generation during prolonged use. This would increase slow muscle endurance by maintaining force production when calcium-activated force production declines and [Pi] increases, such as during long-distance running. For Specific Aim 1 we will test our hypothesis that stretch activation is a previously unknown, alternative way to maintain force production, and that stretch activation contributes to mammalian skeletal muscle endurance. We will test this by measuring SA characteristics and power from skinned and live mouse soleus and extensor digitorum longus fibers subjected to extended use conditions. SA’s mechanism in skeletal muscle is completely unknown. However, our experiments with Drosophila and mice strongly suggest two myosin-based mechanisms for different fiber types. Our proposed soleus mechanism involves a reversible power stroke that does not occur in EDL myosin isoforms. This would enable soleus fibers to store and return energy from stretch in their myosins, increasing muscle efficiency. For Specific Aim 2 we will determine the kinetic and structural mechanisms that differentiate skeletal muscle SA characteristics. Tests of our mechanisms include optical trapping experiments with different myosin isoforms to assess key aspects of our models and fitting cross-bridge model equations to our mammalian SA tension transients. We will test our hypothesis that a specific myosin structural domain is responsible for the SA response differences by measuring SA characteristics of Drosophila muscle expressing chimeric myosins. If our kinetic mechanisms are correct, this structural experiment will determine the region of myosin that determines if a myosin isoform’s power-stroke is reversable. For Specific Aim 3 we will test our hypothesis that disrupted SA properties contribute to hypertrophic cardiomyopathy (HCM) and myosin based skeletal muscle diseases. We will test if the mechanisms of two of our Drosophila HCM models include altered SA characteristics, and create three new Drosophila models where the HCM mutations are in a domain our preliminary results suggest is critical for endowing stretch-activated force. We will test two models of Distal Arthrogryposis, one with a severe and the other a mild phenotype, for alterations to SA. Our combined use of mammalian and Drosophila models is particularly powerful for uncovering new, fundamental knowledge into SA’s roles and mechanisms, and will propel us toward our long-term goal of applying insights from SA to restore impaired muscle function.


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 = $459,324 )
2026	2026	RENSSELAER POLYTECHNIC INSTITUTE	110 8TH ST	TROY	NY	12180	RENSSELAER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/16/2025	NON-COMPETING CONTINUATION	$459,324
														Subtotal = $459,324

Issue Date FY: 2025 ( Subtotal = $522,714 )
2025	2025	RENSSELAER POLYTECHNIC INSTITUTE	110 8TH ST	TROY	NY	12180	RENSSELAER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	12/31/2024	NEW	$522,714
														Subtotal = $522,714

Grand Total All Awards = $982,038

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New mechanisms behind skeletal muscle endurance

Award Number: R01AR083916

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: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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