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T-tubule membrane remodeling in Drosophila myofiber function and models of myopathy

Award Number: R01AR073840
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 Muscles are highly specialized and organized cells that provide contraction essential for animal life. A disruption of the elaborate, functional muscle cell organization underlies human myopathy diseases. In particular, differentiation of the muscle cell membrane into an extensive tubular membrane network called Transverse (T)-tubules is needed to enable signaling that coordinates power of muscle contraction. T-tubule disorganization or loss is observed in certain human skeletal myopathies and cardiovascular diseases, and interestingly, associated mutant genes encode for membrane regulators with known wildtype roles outside of muscle in endocytosis or endosomal trafficking. While there are speculations on mechanisms, it remains to be determined how implicated endocytic functions may contribute to T-tubule maintenance. Relatively little is known about the molecular-genetic basis for how T-tubules form nor the dynamics or remodeling mechanisms in intact muscle in response to muscle cell use, damage or aging. In flies, we uncovered regulated T-tubule remodeling and the identity of specific conserved gene functions involved at distinct disassembly-reassembly stages during a wildtype developmental myofiber remodeling program. Importantly, specific T-tubule remodeling roles for fly homologs of two human genes disrupted in centronuclear myopathy point to the significance of T-tubule dynamics and the ability to study in models of disease. The fly system affords the unique and key advantages of live, in vivo imaging of T-tubule dynamics in intact myofibers within a stereotypical developmental timeframe in combination with a wealth of genetic tools. Following results from genetic screens, we established a new framework understanding of T-tubule dynamics that includes a central role for dynamin large GTPase activity in T-tubule disassembly and subsequent membrane progression into specific endosomal and autophagy trafficking needed for remodeling. Using our innovative genetic, cellular and molecular approaches in intact fly muscles, here we will build on our novel findings to determine the mechanisms and regulation of dynamin-mediated T-tubule disassembly by vesiculation, and establish the identity of a proposed novel Rab35 endosomal pathway and the relationship to autophagy both needed for progression from disassembly to remodeling. Importantly, we will translate our understanding of a developmental program for T-tubule remodeling to adult flight muscle. We will establish conservation and consequences of a pathway activity for T-tubule membrane reorganization in ongoing adult muscle function, with relevance to understanding human muscle 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: 2022 ( Subtotal = $456,653 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	6/7/2022	SUPPLEMENT FOR EXPANSION	$112,529
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/6/2022	NON-COMPETING CONTINUATION	$344,124
														Subtotal = $456,653

Issue Date FY: 2021 ( Subtotal = $449,672 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/11/2021	SUPPLEMENT FOR EXPANSION	$112,500
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/10/2021	NON-COMPETING CONTINUATION	$337,172
														Subtotal = $449,672

Issue Date FY: 2020 ( Subtotal = $431,638 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/26/2020	NON-COMPETING CONTINUATION	$347,508
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	9/7/2020	SUPPLEMENT FOR EXPANSION	$84,130
														Subtotal = $431,638

Issue Date FY: 2019 ( Subtotal = $346,409 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	5/31/2019	NON-COMPETING CONTINUATION	$346,409
														Subtotal = $346,409

Issue Date FY: 2018 ( Subtotal = $345,400 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/9/2018	NEW	$345,400
														Subtotal = $345,400

Grand Total All Awards = $2,029,772

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T-tubule membrane remodeling in Drosophila myofiber function and models of myopathy

Award Number: R01AR073840

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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