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Effects of aging and exercise training on intermuscular adipose tissue (IMAT) in MoTrPAC

Award Number: R01AG077956
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Effects of aging and exercise training on intermuscular adipose tissue (IMAT) in MoTrPAC - Intermuscular adipose tissue (IMAT) is marbled within skeletal muscle and appears to play a key role in the age-induced risk of type 2 diabetes and sarcopenia. What is not known is how IMAT promotes decreased muscle insulin sensitivity and sarcopenia. There is a critical need to address this gap in knowledge to understand how IMAT contributes to the risk of aging-induced sarcopenia and diabetes to inform intervention strategies. The overall objective for this project is to determine the impact of aging and exercise training on IMAT secretion of fibronectin and myostatin and the cellular composition of IMAT. Our central hypothesis is that IMAT secretion of fibronectin promotes muscle insulin resistance, and IMAT secretion of myostatin promotes sarcopenia, both of which are intensified by aging and diminished by exercise. The rationale that underlies the proposed research is that clarifying the extent to which aging and exercise training alter the IMAT secretome and cell composition will inform development of interventions to modify IMAT and improve muscle mass, strength, and insulin sensitivity in older individuals. We propose two specific aims: Specific Aim 1. Determine the impact of age and exercise training on IMAT secretion of fibronectin, IMAT fibroblast composition, and the importance of fibronectin in the IMAT secretome to decrease insulin sensitivity in vitro. Preliminary data inform our working hypothesis that IMAT secretion of fibronectin increases with age due to greater fibroblast content, decreases muscle insulin sensitivity, and is attenuated after exercise training. In vitro experiments will measure the extent to which IMAT fibronectin secretion explains IMAT-induced muscle insulin resistance. We propose a coordinated effort between Colorado and Florida MoTrPAC clinical centers. Both sites will generate IMAT and subcutaneous adipose tissue conditioned media from fresh tissue, followed by conditioned media analyses and testing of its direct metabolic effects in vitro in Colorado. IMAT will also be analyzed using single nuclei RNAseq to measure cell composition. Specific Aim 2 – Evaluate the extent to which age and exercise training alter IMAT secretion of myostatin, IMAT lymphocyte composition, and the potency of myostatin in the IMAT secretome to promote sarcopenia in vitro. We hypothesize that the IMAT secretome promotes sarcopenia via myostatin signaling that increases with age due to greater IMAT lymphocyte content and is attenuated after exercise training. In vitro experiments will determine the degree to which IMAT myostatin secretion explains IMAT-induced sarcopenia outcomes. The proposed research is innovative because it represents a new and substantive departure from the status quo by testing specific IMAT secreted paracrine signals rather than clinical associations with IMAT content. These contributions will be significant by identifying the first IMAT paracrine signals impacting muscle insulin sensitivity and sarcopenia revealing IMAT as a novel target to combat aging-induced sarcopenia and metabolic dysfunction.


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 = $660,365 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	000	4	6/26/2025	NON-COMPETING CONTINUATION	$660,365
														Subtotal = $660,365

Issue Date FY: 2024 ( Subtotal = $685,353 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	000	3	6/13/2024	NON-COMPETING CONTINUATION	$685,353
														Subtotal = $685,353

Issue Date FY: 2023 ( Subtotal = $703,421 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	000	2	5/26/2023	NON-COMPETING CONTINUATION	$703,421
														Subtotal = $703,421

Issue Date FY: 2022 ( Subtotal = $788,166 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	001	1	9/19/2022	NEW	$63,954
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Aging Research	000	1	9/12/2022	NEW	$724,212
														Subtotal = $788,166

Grand Total All Awards = $2,837,305

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Effects of aging and exercise training on intermuscular adipose tissue (IMAT) in MoTrPAC

Award Number: R01AG077956

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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