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Mechanistic-based therapeutic to ameliorate cellular senescence and reverse quadriceps muscle atrophy in humans following ACL injury

Award Number: R01AR086573
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Mechanistic-based therapeutic to ameliorate cellular senescence and reverse quadriceps muscle atrophy in humans following ACL injury - Project Summary Anterior Cruciate Ligament (ACL) injury and subsequent reconstruction result in localized inflammation and alterations within the extracellular matrix which have been linked to protracted quadriceps weakness and atrophy. There is a significant gap in knowledge concerning the signaling cascades and intercellular communication among immune cells (e.g., macrophages), fibro-adipogenic progenitors (FAPs), and satellite cells that directly regulate extracellular matrix remodeling within the quadriceps, limiting progress in the field to address the inceptive events underlying poor functional recovery. Compelling preliminary data identify a subset of immune cells and FAPs that undergo cellular senescence that may underlie a fibrotic and inflammatory muscle phenotype through the induction of senescence associated secretory phenotype (SASP) signaling within the ACL-injury quadriceps. Metformin has been implicated to have positive effects on muscle size and function in aged individuals following a period of disuse by enhancing macrophage function and an attenuated cellular senescent burden by targeting SASP in a variety of muscle interstitial cell types. Whether metformin is capable of modulating extracellular matrix remodeling and immune cell profile following acute ligament injury and reconstruction is unknown. The overarching objective of the current proposal is to define cellular senescence as a modifiable target to improve quadriceps health and function in patients following ACL reconstruction. In this randomized, double blind, placebo-controlled clinical trial, the hypothesis is that treatment with metformin (vs placebo) will mitigate quadriceps cellular senescence and this will enhance ECM remodeling, muscle strength and size following ACL reconstruction. Two interconnected but independent aims will address the overarching hypothesis and provide critical mechanistic insight into the etiology of muscle cellular senescence following injury. Specifically, innovative imaging and singe cell analyses will reveal the impact of metformin treatment on macrophage and FAP cellular senescence and SASP, collagen organization, and muscle recovery following ACL reconstruction. Results from this work will directly support the repurposing of metformin to accelerate functional recovery in patients who have sustained ACL injuries.


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 = $627,006 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/31/2026	NEW	$627,006
														Subtotal = $627,006

Grand Total All Awards = $627,006

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Mechanistic-based therapeutic to ameliorate cellular senescence and reverse quadriceps muscle atrophy in humans following ACL injury

Award Number: R01AR086573

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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