Tuesday, July 1, 2025 7/1/2025

Circadian Clock and Muscle Health

Award Number: R01AR079220
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: 03/15/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Circadian Clock and Muscle Health - We have shown that disruption of the muscle circadian clock mechanism through loss of the core clock gene, Bmal1, is sufficient to induce significant muscle weakness and surprisingly, increased mortality. Based on these findings, the overall objective of this grant is to pursue the fundamental understanding of the role of the muscle circadian clock in regulating a daily program of gene expression and how clock disruption leads to significant muscle weakness and diminished systemic health. We found that MyoD1 can modulate expression of the core clock gene, Bmal1 making it a bona fide tissue- specific circadian clock modifier1. We have also determined that MyoD1 and CLOCK:BMAL1 share peak binding at over 3000 sites across the muscle genome. These new findings provide support for our studies to define the mechanism(s) through which MyoD1 modulates the network properties of the clock mechanism as well as understanding the role of MyoD1 as a clock co-factor in the daily genomic and transcriptomic landscape in adult muscle. Downstream from MyoD1 and the clock factors, my lab has identified two muscle specific genes, Rbm20 and Tcap, that we propose link clock disruption with muscle weakness. Loss of muscle Bmal1, results in significant decreases in Rbm20 and Tcap expression and we find changes in sarcomere structure including variability of sarcomere length, distortions in M and Z lines and altered myofilament orientation. Lastly, the global Bmal1 knock out mouse, Bmal1KO, has been used as a model of advanced aging as it exhibits significant aging-like pathologies and has a median lifespan of 37wks. In preliminary experiments using this global Bmal1 KO mouse we rescued Bmal1 in skeletal muscles using an AAV vector with a muscle specific promoter. We found that this was sufficient to significantly improve muscle strength but also significantly extended lifespan. These are complementary to our findings of increased mortality with loss of muscle Bmal1 and demonstrate that rescuing Bmal1 only in skeletal muscle improves systemic health. In addition, with aging and many chronic diseases exhibiting muscle clock disruption, these results suggest that targeting the muscle clock mechanism holds potential as a translational strategy. We propose to test the following three specific aims: Specific Aim 1: To define the roles of MyoD1 within the core clock mechanism and as a co-factor for the daily transcriptomic landscape in skeletal muscle. Specific Aim 2: To test the clock controlled genes, Rbm20 and/or Tcap, for their roles in sarcomere structure and muscle function. Specific Aim 3: To determine the skeletal muscle specific changes required for improved lifespan in the Bmal1 KO mouse.


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 = $440,026 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/5/2025	NON-COMPETING CONTINUATION	$440,026
2025	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	4/28/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $440,026

Issue Date FY: 2024 ( Subtotal = $578,394 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	7/2/2024	NON-COMPETING CONTINUATION	$36,356
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	2/8/2024	NON-COMPETING CONTINUATION	$467,437
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	4/15/2024	SUPPLEMENT FOR EXPANSION	$74,601
														Subtotal = $578,394

Issue Date FY: 2023 ( Subtotal = $618,132 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/28/2023	NON-COMPETING CONTINUATION	$543,531
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	3/15/2023	SUPPLEMENT FOR EXPANSION	$74,601
														Subtotal = $618,132

Issue Date FY: 2022 ( Subtotal = $604,354 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	2	7/28/2022	SUPPLEMENT FOR EXPANSION	$2,000
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	2	7/27/2022	NON-COMPETING CONTINUATION	$48,161
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/3/2022	NON-COMPETING CONTINUATION	$481,592
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	3/7/2022	SUPPLEMENT FOR EXPANSION	$72,601
														Subtotal = $604,354

Issue Date FY: 2021 ( Subtotal = $539,262 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	9/8/2021	SUPPLEMENT FOR EXPANSION	$37,300
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/14/2021	NEW	$501,962
														Subtotal = $539,262

Grand Total All Awards = $2,780,168

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Circadian Clock and Muscle Health

Award Number: R01AR079220

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: 03/15/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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