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Novel mechanisms regulating muscle growth and regeneration: elucidating the Klotho/Jmjd3/Wnt axis

Award Number: R01AR075768
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project summary The ability of skeletal muscle to grow and respond to injury and disease largely depends on a population of myogenic stem cells, called satellite cells. In developing or injured muscle, satellite cells are highly-activated and proliferative. Some daughter cells then undergo a complex program of differentiation that is necessary to establish or maintain muscle health and function. Perturbations of mechanisms that regulate satellite cell proliferation or differentiation can lead to loss of normal muscle function and, in some cases, reduce lifespan. We have discovered that the protein Klotho regulates satellite cell development in young, healthy muscle. As we explored the mechanisms through which Klotho affects satellite cells, we learned that Klotho reduces expression of an enzyme, Jmjd3, that activates genes by removing a silencing mark from lysine 27 on histone 3 (H3K27). In addition, the Klotho-induced reductions in Jmjd3 are associated with increased H3K27 methylation and reduced expression of Wnt-related genes that regulate myogenesis. Together, the observations suggest a novel mechanism through which myogenesis is regulated, involving signaling through a Klotho/Jmjd3/Wnt-mediated pathway. Furthermore, the potential biological importance of the pathway is emphasized by our findings that the targeted deletion of Jmjd3 in satellite cells produced reductions in Wnt signaling, defects in myogenesis and death in neonatal mice. The central hypothesis of our proposed investigation is that signaling through the Klotho/Jmjd3/Wnt pathway plays an important role in myogenesis by regulating satellite cell numbers and differentiation. Furthermore, we propose that this pathway is conserved throughout life, beginning with the first appearance of satellite cells at the fetal muscle fiber surface and continuing into adulthood, when satellite cells are activated by injury or disease. We propose to test that hypothesis through the following Specific Aims. Aim 1. Determine the effects of modulating Klotho and Jmjd3 on post-natal muscle growth and differentiation. Aim 2. Determine the effects of modulating Klotho and Jmjd3 on muscle regeneration following acute injury. Aim 3. Determine the function of satellite cell Jmjd3 in late, fetal, muscle development. The proposed experiments will establish the importance of a novel mechanism that regulates satellite cell development and response to muscle injury. We believe that the outcomes of this investigation will deepen our knowledge of vital mechanisms that regulate muscle development and adaptation and will also provide new insights into the response of muscle to injury and disease.


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: 2024 ( Subtotal = $308,880 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/22/2024	NON-COMPETING CONTINUATION	$308,880
														Subtotal = $308,880

Issue Date FY: 2023 ( Subtotal = $343,200 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	5/18/2023	NON-COMPETING CONTINUATION	$343,200
														Subtotal = $343,200

Issue Date FY: 2022 ( Subtotal = $339,768 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/3/2022	NON-COMPETING CONTINUATION	$339,768
														Subtotal = $339,768

Issue Date FY: 2021 ( Subtotal = $332,904 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/7/2021	NON-COMPETING CONTINUATION	$332,904
														Subtotal = $332,904

Issue Date FY: 2020 ( Subtotal = $343,200 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/13/2020	NEW	$343,200
														Subtotal = $343,200

Grand Total All Awards = $1,667,952

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Novel mechanisms regulating muscle growth and regeneration: elucidating the Klotho/Jmjd3/Wnt axis

Award Number: R01AR075768

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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