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Skeletal Muscle as a Target for Cardio-Metabolic Disease in Sarcopenic Obesity

Award Number: K01AG064121
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Skeletal Muscle as a Target for Cardio-Metabolic Disease in Sarcopenic Obesity - The objective of this application is to examine how augmented muscle mass, a by-product of the exercise intervention commonly prescribed for treatment of obesity and sarcopenia, can prevent and rescue metabolic and vascular dysfunction in sarcopenic obesity. The core hypothesis of this application is that targeting skeletal muscle function in aging can ameliorate metabolic dysfunction and oxidant-induced hypertension in obesity and lay the groundwork for establishment of an independent research program directed toward determining if obesity-derived cardiometabolic dysfunction can be rescued through augmented mass with aging and specific fiber types. The goals of this application will be accomplished by examining the effect of augmented muscle mass, through myostatin deletion, on cardiometabolic function in a mouse model of obesity (the db/db mouse). Experimental methods include in vivo blood pressure using telemetry in conscious mice, vascular function assessments using pressure myography of isolated vessels, and metabolic function using metabolic chambers, glucose tolerance tests, whole body quantification of lean mass and adiposity via DXA Piximus, and blood lipid profiles. Our data indicate that increasing muscle mass in obese mice protects against the loss of muscle mass and strength, glycemic control and vascular dysfunction, which accompany obesity in the db/db mouse. Importantly, our preliminary data indicate that these improvements to metabolic and cardiovascular function prevent hypertension in the db/db mouse. Further, this application will determine the relative contribution to organ specific oxidant stress, namely vascular NOX1 and renal NOX4 in a model of sarcopenic obesity. The model currently used (constitutive myostatin deletion) involves lifelong augmented muscle. A key question remains unanswered; can augmented muscle rescue/reverse obesity-derived cardiovascular dysfunction or is lifelong fitness essential? The applicant intends to focus his transition to independence on answering these key questions. I will use a novel inducible knockout of myostatin in a db/db mouse to determine if augmented muscle mass can rescue metabolic and vascular dysfunction after development of a fully obese phenotype. This will serve to mimic the patient population and allow for results to translate to the clinic. Additionally, literature suggests that skeletal muscle fiber type plays a crucial role in outcomes. The myostatin model used results in predominantly glycolytic skeletal muscle expansion and it would be advantageous to determine if a mouse model of obesity with predominantly oxidative skeletal muscle expansion (PGC1) would have similar cardiometabolic improvements.


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 = $0 )
2025	2024	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Aging Research	000	5	9/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $128,772 )
2024	2024	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Aging Research	000	5	7/8/2024	NON-COMPETING CONTINUATION	$128,772
														Subtotal = $128,772

Issue Date FY: 2023 ( Subtotal = $128,772 )
2023	2023	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Aging Research	000	4	5/10/2023	NON-COMPETING CONTINUATION	$128,772
														Subtotal = $128,772

Issue Date FY: 2022 ( Subtotal = $128,772 )
2022	2022	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Aging Research	000	3	5/17/2022	NON-COMPETING CONTINUATION	$128,772
														Subtotal = $128,772

Issue Date FY: 2021 ( Subtotal = $128,772 )
2021	2021	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Aging Research	000	2	5/19/2021	NON-COMPETING CONTINUATION	$128,772
														Subtotal = $128,772

Issue Date FY: 2020 ( Subtotal = $128,772 )
2020	2020	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Aging Research	000	1	7/22/2020	NEW	$128,772
2020	2020	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Aging Research	001	1	8/3/2020	NEW	$0
														Subtotal = $128,772

Grand Total All Awards = $643,860

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Skeletal Muscle as a Target for Cardio-Metabolic Disease in Sarcopenic Obesity

Award Number: K01AG064121

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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