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PHD2 mediated loss of hypoxia signaling limits skeletal muscle regeneration and exercise response in aging

Award Number: R01AG078307
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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PHD2 mediated loss of hypoxia signaling limits skeletal muscle regeneration and exercise response in aging - PROJECT SUMMARY/ABSTRACT I am interested in developing novel treatment strategies for maintaining muscle mass and function in the elderly population. My lab utilizes murine models of aging to investigate mechanisms on how aging-associated loss of hypoxia signaling in skeletal muscle affects two key factors in maintenance of muscle mass and function: (1) skeletal muscle regeneration and (2) adaptation to aerobic exercise. Prolyl hydroxylase domain enzyme (PHD)2 increases profoundly in skeletal muscle with aging and is a key regulator of the hypoxia signaling pathway. This increase in skeletal muscle PHD2 leads to loss of hypoxia inducible factor (HIF)-1, a central transcription factor responsible for downstream hypoxia pathway signaling. Using a murine model of aging and genetically modified mice, we have demonstrated that a muscle specific increase in PHD2 recapitulates diminished skeletal muscle regeneration and loss of aerobic exercise adaptation as seen in aging. Building on these intriguing pilot data, the central goals of this project are to (1) mechanistically define the role of PHD2 and its impact on muscle regeneration in aging, (2) determine whether PHD2 inhibition preserves skeletal muscle myogenic potential with aging, and (3) evaluate if increased skeletal muscle PHD2 in aging limits muscle adaptation in response to aerobic exercise. Importantly, transcriptome analysis in humans also demonstrates decreased hypoxia signaling in old skeletal muscle, suggesting translational potential for hypoxia signaling targets. As FDA approved PHD2 inhibitors are available, an improved mechanistic understanding of hypoxia signaling as it relates to skeletal muscle regeneration and exercise response may offer therapeutic opportunities for elderly patients suffering from loss of muscle function with aging.


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 = $384,166 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	3	3/6/2025	NON-COMPETING CONTINUATION	$352,805
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	001	3	6/17/2025	NON-COMPETING CONTINUATION	$31,361
														Subtotal = $384,166

Issue Date FY: 2024 ( Subtotal = $395,166 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	2	4/19/2024	NON-COMPETING CONTINUATION	$395,166
														Subtotal = $395,166

Issue Date FY: 2023 ( Subtotal = $395,166 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Aging Research	000	1	3/24/2023	NEW	$395,166
														Subtotal = $395,166

Grand Total All Awards = $1,174,498

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PHD2 mediated loss of hypoxia signaling limits skeletal muscle regeneration and exercise response in aging

Award Number: R01AG078307

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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