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Mediators of Muscle Rejuvenation with Aging

Award Number: R01AG080047
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Mediators of Muscle Rejuvenation with Aging - Project Summary Tissue function declines with age which has deleterious effects that can be mitigated by exercise. The molecular causes of functional decline with age and the extent to which tissue aging can be mitigated by exercise is unclear. The reversal of cells to a younger epigenetic and phenotypic age is controlled by Yamanaka factors (OCT3/4, SOX2, KLF4, and MYC, or “OKSM”). In skeletal muscle, the most voluminous tissue in the body, MYC is the only Yamanaka factor induced by exercise. MYC also becomes less responsive to exercise with advancing age. The purpose of this proposal is to examine the role that MYC plays in skeletal muscle functional, metabolic, cellular, and molecular plasticity throughout the lifespan. To answer our research questions, we developed a mouse model that allows for pulsatile control of MYC specifically in skeletal muscle fibers simultaneous with fluorescent labeling of muscle fiber nuclei (myonuclei) for purification and downstream analyses. We also developed a novel murine model of voluntary exercise for aged mice. We will perform: 1) functional, bioenergetic, and cellular analyses, 2) single myonuclear RNA-sequencing, and 3) global DNA methylation and methylation clock analyses in myonuclei after weekly pulsatile MYC induction and exercise throughout the lifespan. We hypothesize that MYC induction in muscle will mimic functional and cellular aspects of exercise adaptation throughout the lifespan and amplify the effects of exercise training. MYC will mediate youthfulness at several molecular levels, including biological aging determined by DNA methylation “clock” age. Furthemore, we hypothesize that MYC induction late in life is sufficient to reverse molecular and cellular aspects of muscle aging. Our experiments will provide fundamental information on the role of MYC in skeletal muscle and its capacity for epigenetic and transcriptional age reversal in myonuclei. We expect that our innovative approaches and comprehensive hypothesis-driven -omics analyses will serve as a foundation for understanding skeletal muscle mass regulation with aging, and provide new directions for exploring what mediates the age-defying effects of exercise.


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: 2025 ( Subtotal = $792,024 )
2025	2025	UNIVERSITY OF ARKANSAS	1125 W MAPLE ST STE 316	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Aging Research	002	3	6/12/2025	NON-COMPETING CONTINUATION	$52,942
2025	2025	UNIVERSITY OF ARKANSAS	1125 W MAPLE ST STE 316	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Aging Research	000	2	3/17/2025	SUPPLEMENT FOR EXPANSION	$143,480
2025	2025	UNIVERSITY OF ARKANSAS	1125 W MAPLE ST STE 316	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Aging Research	001	3	4/16/2025	NON-COMPETING CONTINUATION	$595,602
														Subtotal = $792,024

Issue Date FY: 2024 ( Subtotal = $492,393 )
2024	2024	UNIVERSITY OF ARKANSAS	1125 W MAPLE ST STE 316	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Aging Research	000	2	5/2/2024	NON-COMPETING CONTINUATION	$492,393
														Subtotal = $492,393

Issue Date FY: 2023 ( Subtotal = $492,393 )
2023	2023	UNIVERSITY OF ARKANSAS SYSTEM	1125 WEST MAPLE STE 210	FAYETTEVILLE	AR	72701	WASHINGTON	USA	Aging Research	000	1	7/18/2023	NEW	$492,393
														Subtotal = $492,393

Grand Total All Awards = $1,776,810

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Mediators of Muscle Rejuvenation with Aging

Award Number: R01AG080047

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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