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Mechanisms and Function of Myonuclear Positioning

Award Number: R01AR068128
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: 09/01/2014
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Mechanisms and Function of Myonuclear Positioning - PROJECT SUMMARY/ABSTRACT Our long-term goal is to significantly impact the fundamental knowledge of muscle biology and provide new approaches for disease treatment. Striated muscle fibers are large multinucleated cells and possess a highly organized cytoarchitecture containing organelles positioned for optimal muscle function. This positioning is particularly evident in the placement of myonuclei, which reside above the sarcomere at the periphery of the myofiber and are positioned to maximize their internuclear distance. Our objective is the identification of mechanisms responsible for myonuclear movement and positioning. Centrally located myonuclei have been used for decades as a hallmark of muscle disease. However, much remains to be learned about the mechanisms that control myonuclear movement normally and the contribution of aberrant myonuclear position to the etiology and/or progression of muscle disease. Building on our published results over funding period (e.g. Metzger et al., 2012; Folker et al., 2012, 2014; Schulman et al., 2013, 2014; Azevedo et al., 2016; Manhart et al., 2018, 2020; Rosen et al., 2019), our specific aims are to first address mechanistically how tendon and motoneurons signal to the myofiber to fine-tune myonuclear positioning. We identified two signaling pathways at the myotendinous junction that regulate nuclear positioning. Likewise, we will dissect the contribution of the motoneuron to nuclear placement. Secondly, we will examine why muscles fail to function optimally when myonuclei are mispositioned. Muscle physiology will be assayed through testing mitochondrial function via quantification of ATP and ROS levels and by testing neuromuscular communication via electrophysiological approaches. We will also investigate the input to muscle function of specific metabolic and signaling proteins that we identified are misregulated as a result of mispositioned myonuclei. Thirdly, we will push forward our dissection of the myonuclear positioning mechanisms from fly to the human system. We will employ human 3D muscle cultures that are co-cultured with motoneurons to define and then perturb myonuclear movement and positioning as the myofibers develop. Our methodologies take advantage of cutting edge, in vivo time lapse imaging approaches that we have developed in Drosophila and will also apply to human 3D cultures to follow myonuclear movement and cytoskeletal dynamics. We will employ the genetic resources available in Drosophila and human cultures to manipulate genes, processes, and cell types for our analyses. These genetic experiments will be supported by biochemical and cell biological approaches. Together the work outlined in this proposal will shed new light on this little understood, but important area of muscle biology. The results of this research will permit us to highlight genes and mechanisms that are candidates for changes associated with different human muscle diseases.


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 = $547,414 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	1/28/2025	NON-COMPETING CONTINUATION	$547,414
														Subtotal = $547,414

Issue Date FY: 2024 ( Subtotal = $589,990 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	1/10/2024	NON-COMPETING CONTINUATION	$547,414
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	9	6/4/2024	NON-COMPETING CONTINUATION	$42,576
														Subtotal = $589,990

Issue Date FY: 2023 ( Subtotal = $608,237 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	1/16/2023	NON-COMPETING CONTINUATION	$547,414
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	8	2/22/2023	NON-COMPETING CONTINUATION	$60,823
														Subtotal = $608,237

Issue Date FY: 2022 ( Subtotal = $651,787 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	7	5/25/2022	NON-COMPETING CONTINUATION	$59,253
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	1/28/2022	NON-COMPETING CONTINUATION	$592,534
														Subtotal = $651,787

Issue Date FY: 2021 ( Subtotal = $677,568 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	3/1/2021	COMPETING CONTINUATION	$677,568
2021	2018	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	11/10/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $677,568

Issue Date FY: 2018 ( Subtotal = $414,150 )
2018	2018	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/13/2018	NON-COMPETING CONTINUATION	$414,150
														Subtotal = $414,150

Issue Date FY: 2017 ( Subtotal = $417,960 )
2017	2017	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/29/2017	NON-COMPETING CONTINUATION	$417,960
														Subtotal = $417,960

Issue Date FY: 2016 ( Subtotal = $423,934 )
2016	2016	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/22/2016	NON-COMPETING CONTINUATION	$423,934
														Subtotal = $423,934

Issue Date FY: 2015 ( Subtotal = $403,069 )
2015	2015	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/26/2015	NON-COMPETING CONTINUATION	$403,069
														Subtotal = $403,069

Issue Date FY: 2014 ( Subtotal = $407,518 )
2014	2014	SLOAN KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/20/2014	NEW	$407,518
														Subtotal = $407,518

Grand Total All Awards = $5,141,627

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Mechanisms and Function of Myonuclear Positioning

Award Number: R01AR068128

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: 09/01/2014

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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