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The essentiality of serine and glycine for skeletal muscle regeneration in aging

Award Number: R01AG075059
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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The essentiality of serine and glycine for skeletal muscle regeneration in aging - PROJECT SUMMARY/ABSTRACT Impaired skeletal muscle regeneration and associated pathological tissue remodeling (loss of muscle, gain of fibrotic and adipose tissues) following injury underlie functional and metabolic decline—hallmarks of aging. Regeneration is dependent on a well-orchestrated myogenic program that includes the activation and expansion of skeletal muscle stem cells/progenitor cells (MPCs) and terminal differentiation of MPCs into mature multinucleated muscle cells. We previously demonstrated that MPCs rely on extracellular availability of the nutritionally, non-essential amino acids L-serine (Ser) and glycine (Gly). Decreased availability of Ser/Gly impairs MPC expansion, induces intramuscular adipocytes following injury, and induces toxic deoxysphingolipid accumulation in the muscle. Further, we demonstrated that endogenous Ser/Gly levels decline with age. The metabolic product (i.e. requirement) of Ser/Gly for MPC expansion and the efficacy of dietary Ser/Gly for muscle regeneration and the cell (MPC)-extrinsic environment need to be resolved. We propose to use isotope tracing of Ser and Gly to define the metabolic requirement of Ser/Gly for MPC population expansion. Further, using models that we have demonstrated reduce (depleted diet) or enhance (supplemented diet) endogenous Ser/Gly levels, we will quantify the effects of Ser/Gly availability on age- and injury-related muscle regeneration and the cell (MPC)-extrinsic muscle environment. Based on preliminary data, we hypothesize that MPCs require glutathione synthesis, from extracellular Ser and Gly, to mitigate oxidative stress. Additionally, we hypothesize that diet-induced reduction of endogenous Ser/Gly exacerbates age-related (i) impairments in muscle regeneration and (ii) toxic non-canonical sphingolipids in the cell-extrinsic muscle environment. Further, we expect Ser/Gly supplementation will counter these effects. To capture the efficacy of dietary Ser/Gly to modulate age-related impairments in muscle regeneration and remodeling we will use novel sphingolipidome profiling and transcriptomics. Successful completion of this project will transform the fundamental understanding of the metabolic essentiality of Ser and Gly for skeletal muscle regeneration and the relationship of this loss to age- related muscle deterioration. The results will enable testable scientifically grounded therapies to improve the regenerative capacity in populations that have impaired muscle regeneration, such as older adults.


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 = $294,048 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	4	12/9/2024	NON-COMPETING CONTINUATION	$294,048
														Subtotal = $294,048

Issue Date FY: 2024 ( Subtotal = $421,955 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	3	11/15/2023	NON-COMPETING CONTINUATION	$379,759
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	001	3	5/2/2024	NON-COMPETING CONTINUATION	$42,196
														Subtotal = $421,955

Issue Date FY: 2023 ( Subtotal = $423,844 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	2	1/18/2023	NON-COMPETING CONTINUATION	$423,844
														Subtotal = $423,844

Issue Date FY: 2022 ( Subtotal = $350,990 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	1	1/4/2022	NEW	$350,990
														Subtotal = $350,990

Grand Total All Awards = $1,490,837

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The essentiality of serine and glycine for skeletal muscle regeneration in aging

Award Number: R01AG075059

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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