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Motoneuronal mechanisms underlying age-related muscle weakness

Award Number: R01AG067758
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Motoneuronal mechanisms underlying age-related muscle weakness - ABSTRACT Forty-two percent of older adults have one or more physical limitations performing daily tasks that are essential for maintaining independence in the community. Age-related weakness is an important contributor to physical impairments, as weakness predisposes older adults to a 4-fold increase in physical limitations. For decades, age-related weakness was largely attributed to the loss of muscle mass, but recent data indicates that mass plays a lesser role than originally thought, highlighting that other neurological and/or muscle quality related factors are critical in the development of weakness. Despite the significance of maintaining physical strength in aging, the majority of the research has focused on maintaining muscle mass. Considerably less is known regarding the neural mechanisms potentially contributing to age-related weakness. This knowledge gap represents a barrier to the development of new interventions to enhance strength and function in older adults. In this application we will test the central hypothesis that age-related weakness is due, in part, to upregulation in motor neuron (MN) SK channels (small conductance calcium-activated potassium channels) that results in type- dependent reductions in intrinsic MN excitability and firing rates. Prior work indicates that aging results in reduced number of MUs (the α-MN and the muscle fibers that it innervates) and lower firing rates. However, prior work has stopped short of determining whether age-related reductions in MU numbers are related to clinically- meaningful weakness, and determining the ionic mechanisms underlying reduced MN firing rates in aging. In this application we propose a series of parallel, cross-sectional and longitudinal animal (Aims 1 and 2) and human experiments (Aim 3) to test our central hypothesis. Aim 1 will determine if MN excitability dysfunction is involved in age-related weakness and determine its temporal relationship to MU loss in mice. Aim 2 will identify the cellular mechanisms underlying MN excitability dysfunction in aged mice. Aim 3 will determine the role of MN excitability and number in clinically-meaningful, age-related weakness in older adults. This work aligns with stated goals from the National Institute on Aging (NIA). The knowledge to be gained from this work has the potential to fundamentally shift the fields of sarcopenia and frailty research towards MN excitability as an early biomarker for the development of weakness, and identifying key MN ion channels that could serve as a neurotherapeutic targets for treating or preventing age-related weakness.


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 = $552,140 )
2025	2025	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	001	5	6/17/2025	NON-COMPETING CONTINUATION	$45,073
2025	2025	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	000	5	3/11/2025	NON-COMPETING CONTINUATION	$507,067
														Subtotal = $552,140

Issue Date FY: 2024 ( Subtotal = $577,983 )
2024	2024	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	000	4	3/14/2024	NON-COMPETING CONTINUATION	$520,185
2024	2024	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	001	4	7/1/2024	NON-COMPETING CONTINUATION	$57,798
														Subtotal = $577,983

Issue Date FY: 2023 ( Subtotal = $712,719 )
2023	2023	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	001	3	3/24/2023	SUPPLEMENT FOR EXPANSION	$118,678
2023	2023	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	000	3	3/21/2023	NON-COMPETING CONTINUATION	$594,041
														Subtotal = $712,719

Issue Date FY: 2022 ( Subtotal = $1,562,422 )
2022	2022	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	005	2	6/15/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	001	2	4/21/2022	SUPPLEMENT FOR EXPANSION	$118,678
2022	2022	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	000	2	4/20/2022	NON-COMPETING CONTINUATION	$608,760
2022	2022	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	003	2	5/26/2022	SUPPLEMENT FOR EXPANSION	$299,991
2022	2022	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	004	2	6/14/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	002	2	5/23/2022	SUPPLEMENT FOR EXPANSION	$300,063
2022	2022	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	006	2	8/11/2022	SUPPLEMENT FOR EXPANSION	$234,930
														Subtotal = $1,562,422

Issue Date FY: 2021 ( Subtotal = $648,106 )
2021	2021	OHIO UNIVERSITY	1 OHIO UNIVERSITY	ATHENS	OH	45701	ATHENS	USA	Aging Research	000	1	5/18/2021	NEW	$648,106
														Subtotal = $648,106

Grand Total All Awards = $4,053,370

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Motoneuronal mechanisms underlying age-related muscle weakness

Award Number: R01AG067758

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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