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Role of skeletal muscle mitophagy in healthy aging

Award Number: R00AG057825
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Role of skeletal muscle mitophagy in healthy aging - Project Summary Mitochondrial quality in skeletal muscle progressively declines with advancing age, leading to tissue dysfunction and disease. Several lines of evidence suggest poor mitochondrial quality in skeletal muscle of old animals and humans is due in large part to an impaired or insufficient capacity to degrade damaged/dysfunctional mitochondria via mitophagy. Exercise promotes mitochondrial quality leading to healthy aging but the underlying mechanisms and how they differ with age is not well defined, particularly in regards to mitophagy, restraining development of effective interventions. Building upon my previous work demonstrating that exercise does indeed promote mitophagy in skeletal muscle but only of a small fraction of the total mitochondrial reticulum, I show here evidence of an Ampk-dependent mechanism that may distinguish damaged vs. healthy regions of the mitochondrial reticulum that is lost with age. Additionally, I show that key downstream mitophagy-related factors that are recruited to mitochondria in skeletal muscle with exercise are required for mitochondrial quality and healthy aging in d. melanogaster. The proposed research tests the hypothesis that recognition of damaged regions of the mitochondrial reticulum in response to exercise is impaired in skeletal muscle of old mice, blunting local recruitment of key mitophagy proteins, leading to poor mitochondrial quality. These studies will provide insight into novel regulation of skeletal muscle mitophagy in response to exercise and lay a foundation for the development of targeted interventions to promote mitochondrial quality in skeletal muscle for improved tissue function and healthy aging. During the mentored phase, I will employ state-of-the-art two-photon microscopy to perform intravital and ex vivo fluorescent lifetime microscopy of Ampk activity on mitochondria in skeletal muscle of young and old mice to determine the age-dependent, localized response of Ampk to sustained contraction and mitochondrial damage. Also, I will continue my professional and scientific development in preparation for the independent phase with continuous guidance from my mentoring committee. During the independent phase, I will employ co-somatic gene transfer in skeletal muscle of young and old wild-type mice as well as skeletal muscle-specific, conditional Ulk1 knock-out mice to determine the age-dependent regulation for the recruitment of downstream mitophagy-related factors to mitochondria in skeletal muscle in response to exercise. Also, I will develop novel phospho-mimetic constructs to constitutively activate or inhibit mitophagy-related factors Atg9 and Atg2 in young and old mouse skeletal muscle and investigate their necessity and sufficiency for the breakdown of mitochondrial proteins and maintenance of mitochondrial quality, via state-of-the-art high resolution proteomic and confocal imaging approaches. Collectively, these studies and career development activities will foster my continued scientific and professional training, leading to a successful independent, academic research program.


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: 2024 ( Subtotal = -$52,874 )
2024	2022	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Aging Research	000	5	9/9/2024	NON-COMPETING CONTINUATION	-$52,874
														Subtotal = -$52,874

Issue Date FY: 2022 ( Subtotal = $229,602 )
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Aging Research	000	5	4/11/2022	NON-COMPETING CONTINUATION	$229,602
														Subtotal = $229,602

Issue Date FY: 2021 ( Subtotal = $238,200 )
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Aging Research	000	4	4/8/2021	NON-COMPETING CONTINUATION	$238,200
														Subtotal = $238,200

Issue Date FY: 2020 ( Subtotal = $275,261 )
2020	2020	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Aging Research	003	3	5/19/2020	EXTENSION WITH OR WITHOUT FUNDS	$0
2020	2020	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Aging Research	001	3	3/31/2020	EXTENSION WITH OR WITHOUT FUNDS	$0
2020	2020	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Aging Research	002	3	5/13/2020	EXTENSION WITH OR WITHOUT FUNDS	$49,934
2020	2020	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Aging Research	000	3	3/20/2020	EXTENSION WITH OR WITHOUT FUNDS	$225,327
														Subtotal = $275,261

Grand Total All Awards = $690,189

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Role of skeletal muscle mitophagy in healthy aging

Award Number: R00AG057825

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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