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Mechanisms for Impaired Adaptation to Aerobic Exercise with Metabolic Disease

Award Number: R01DK124258
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Mechanisms for Impaired Adaptation to Aerobic Exercise with Metabolic Disease - PROJECT SUMMARY/ABSTRACT Exercise capacity, also known as cardiorespiratory fitness, has emerged as one of the single best predictors of health and longevity. Low exercise capacity is a strong risk factor for the development of cardiovascular disease and overall mortality. Aerobic exercise training is the only effective treatment to increase exercise capacity and reduce the health risks associated with low exercise capacity. However, even when levels of physical activity are matched, exercise capacity remains lower in people with metabolic diseases such as Type 1 and Type 2 diabetes compared to those without metabolic disease, suggesting a phenotype of “low response to training”. The goal of this investigation is to determine the mechanisms that contribute to low response to training in metabolic disease, and develop treatment strategies to improve the response to exercise. Clinical investigations and our data from animal models suggest that chronically high blood glucose levels (i.e. hyperglycemia) may be a cause for low response to training by blunting beneficial adaptations that normally occur with exercise in tissues like skeletal muscle. We hypothesize that hyperglycemia causes glycation and accumulation of the extracellular matrix (ECM) in muscle, and in turn, these glucose-induced ECM alterations can prevent tissue remodeling with exercise in 3 distinct ways: 1) Altering muscle signal transduction via a newly discovered JNK/SMAD mechanical signaling axis; 2) Impairing the function of muscle progenitor and endothelial cells; and 3) Reducing levels of circulating ECM remodeling proteins. One specific aim is to determine whether blood glucose lowering treatments can improve exercise capacity and muscle remodeling in response to exercise in animal models of metabolic disease. A second aim is to determine the cellular and molecular mechanisms in muscle that contribute to low exercise response under conditions of hyperglycemia. Finally, we will use advanced proteomic screening combined with in vitro methodology to identify circulating mediators of low response to training in humans subjects. Hyperglycemia is becoming more common as rates of metabolic disease rise globally. This may lead to a population that is increasingly resistant to improved exercise capacity with training, and the associated reduction in health risk. Despite significant clinical evidence linking chronic hyperglycemia to the “low-response to training” phenotype, little is known about the molecular mechanisms underlying these associations. This project will significantly advance our understanding of the mechanisms that cause low response to training in people with metabolic disease, and identify treatments to improve exercise capacity, health span, and longevity.


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	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	6/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$92,308
2025	2023	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/17/2025	NON-COMPETING CONTINUATION	-$92,308
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $475,718 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	5	9/10/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	8/29/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$475,718
2024	2023	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/28/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $475,718

Issue Date FY: 2023 ( Subtotal = $528,727 )
2023	2023	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/2/2023	NON-COMPETING CONTINUATION	$528,727
														Subtotal = $528,727

Issue Date FY: 2022 ( Subtotal = $528,727 )
2022	2022	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/10/2022	NON-COMPETING CONTINUATION	$528,727
														Subtotal = $528,727

Issue Date FY: 2021 ( Subtotal = $550,129 )
2021	2021	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/9/2021	NON-COMPETING CONTINUATION	$550,129
														Subtotal = $550,129

Issue Date FY: 2020 ( Subtotal = $549,519 )
2020	2020	JOSLIN DIABETES CENTER, INC.	1 JOSLIN PL	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/11/2020	NEW	$549,519
														Subtotal = $549,519

Grand Total All Awards = $2,632,820

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Mechanisms for Impaired Adaptation to Aerobic Exercise with Metabolic Disease

Award Number: R01DK124258

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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