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Reversing Skeletal Muscle Myopathy by Hydrogen Sulfide

Award Number: R01AR071789
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2018
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Reversing Skeletal Muscle Myopathy by Hydrogen Sulfide - Children born with severe homocystinuria due to homozygous cystathionine beta synthase deficiency (CBS-/-) exhibit poor body weights, skeletal muscle myopathy and die in teenage. Although mice with homozygous CBS mutation die shortly after birth, the heterozygous CBS-/+ survives. Our preliminary data suggests that enzymes, CBS and cystathionine gamma-lyase (CSE) that irreversibly remove homocysteine (Hcy) by converting to hydrogen sulfide (H2S), are decreased in skeletal muscle. Although lowering of Hcy levels and generation of H2S is beneficial, the mechanism by which HHcy causes of skeletal muscle wasting and frailty is unknown. The long-term goal of this project is to understand the mechanism of muscle wasting in HHcy and evaluate the potential beneficial effects of H2S signaling in reversing skeletal muscle wasting and myopathy. The central hypothesis of this proposal is that HHcy causes skeletal muscle deterioration by compromising vasculogenesis, by enhancing muscle atrophy and by limiting skeletal muscle regeneration and H2S reverses these changes. We will test this hypothesis by following three specific aims: Specific Aim #1: To determine whether the HHcy inhibits muscle specific AKT, HIF-1, and AMPK signaling and impairs vasculogenesis and H2S reverses impaired vasculogenesis. Specific Aim #2: To determine whether the HHcy attenuates PGC-1 signaling and instigates atrogene expression and causes muscular atrophy and H2S mitigates muscle atrophy. Specific Aim #3: To determine whether the HHcy enhances TGF-1 signaling and myostatin levels, thereby suppresses muscle regeneration and H2S ameliorates these changes.


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 = -$32,327 )
2025	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/25/2025	NON-COMPETING CONTINUATION	-$32,327
														Subtotal = -$32,327

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $338,800 )
2023	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	2/1/2023	NON-COMPETING CONTINUATION	$304,920
2023	2023	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	2/23/2023	NON-COMPETING CONTINUATION	$33,880
														Subtotal = $338,800

Issue Date FY: 2022 ( Subtotal = $335,412 )
2022	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/28/2022	NON-COMPETING CONTINUATION	$304,920
2022	2022	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	5/25/2022	NON-COMPETING CONTINUATION	$30,492
														Subtotal = $335,412

Issue Date FY: 2021 ( Subtotal = $328,636 )
2021	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/19/2021	NON-COMPETING CONTINUATION	$304,920
2021	2021	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/9/2021	NON-COMPETING CONTINUATION	$23,716
														Subtotal = $328,636

Issue Date FY: 2020 ( Subtotal = $338,800 )
2020	2020	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/24/2020	NON-COMPETING CONTINUATION	$304,920
2020	2020	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/22/2020	NON-COMPETING CONTINUATION	$33,880
														Subtotal = $338,800

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/2/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $338,800 )
2018	2018	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/21/2018	NEW	$338,800
														Subtotal = $338,800

Grand Total All Awards = $1,648,121

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Reversing Skeletal Muscle Myopathy by Hydrogen Sulfide

Award Number: R01AR071789

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/21/2018

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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