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Myosin Gene Diversity and Function

Award Number: R01GM029090
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/1981
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Myosin Gene Diversity and Function - PROJECT SUMMARY Muscles are highly plastic tissues that respond rapidly to a wide variety of stimuli by altering their composition, contractility, and metabolism. For example, myosin is the most abundant protein in muscle, and during development, 50% of embryonic myosin is replaced in 3 hours by adult myosins. This is remarkable given that the average half-life of muscle myosin in vivo at baseline can be >1 month. Also, in terminally differentiated cardiac and skeletal muscle cells, protein turnover is essential to repair and replace damaged proteins. Little is known about the rates and mechanisms of protein exchange and turnover in different muscles. We propose to study these processes in cardiac, fast and slow skeletal muscles, and determine how they are influenced by biological sex, activity, and disease-causing sarcomeric mutations. We have developed two powerful methods to measure protein homeostasis in muscle cells. First, we will use multi-isotope imaging mass spectrometry electron microscopy (MIMS-EM) in mice to define the spatiotemporal distributions of old and new sarcomeres. MIMS-EM will be complemented by stable isotope labeling to determine turnover rates of individual proteins. Our data indicate muscle-specific differences for sarcomeric protein turnover. The fastest rates occur in cardiac muscle, followed by slow skeletal muscles and then fast skeletal muscles. In a second approach, we developed single myosin molecule live cell imaging in muscle cells to directly measure sarcomere dynamics. We will also measure the contributions of the ubiquitin (Ub) proteasome system and autophagy to exchange and turnover. We will investigate which factors (biological sex and muscle use) regulate turnover rates between different muscles. We will determine the impact of ubiquitination of myosin on sarcomere dynamics. We will focus on myosin since it is a major determinant of muscle physiology and function. Moreover, >500 mutations in myosin genes cause a variety of cardiomyopathies or skeletal myopathies. Our data show that myosin is heavily ubiquitinated in the human heart, with 68 unique sites. We will carry out Ub-proteomics on human hearts with and without myosin mutations to assess whether ubiquitinated myosin and sarcomeric proteins are altered in disease. We have mutagenized the two most heavily ubiquitinated lysines to arginines and have shown that these mutations delay turnover in cardiac myocytes. Finally, we will define the mechanisms whereby the R1500P MYH7 rod mutation causes skeletal myopathy while R1500W causes cardiomyopathy. We have shown that the R1500P mutation affects myosin conformation energetic states and used a small molecule myosin inhibitor in our R1500P mouse model that improves its phenotypes. We will determine the turnover rates of both mutant myosin proteins in cardiac myocytes and skeletal myotubes. Finally, we will quantify sarcomere dynamics in these two cell types using single myosin molecule imaging. The long-term goal of this work is to understand how muscles remodel their sarcomeres to meet the demands of changing environments.


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 = $515,855 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	002	43	5/12/2025	NON-COMPETING CONTINUATION	$515,855
2025	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	42	4/10/2025	COMPETING CONTINUATION	$19,247
2025	2023	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	41	4/10/2025	SUPPLEMENT FOR EXPANSION	-$19,247
														Subtotal = $515,855

Issue Date FY: 2024 ( Subtotal = $563,605 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	42	5/24/2024	COMPETING CONTINUATION	$563,605
														Subtotal = $563,605

Issue Date FY: 2023 ( Subtotal = $773,029 )
2023	2023	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	41	9/14/2023	SUPPLEMENT FOR EXPANSION	$232,500
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	41	5/8/2023	NON-COMPETING CONTINUATION	$540,529
														Subtotal = $773,029

Issue Date FY: 2022 ( Subtotal = $520,996 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	40	5/19/2022	NON-COMPETING CONTINUATION	$520,996
														Subtotal = $520,996

Issue Date FY: 2021 ( Subtotal = $529,803 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	39	5/3/2021	NON-COMPETING CONTINUATION	$529,803
2021	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	002	38	5/17/2021	COMPETING CONTINUATION	$104,550
2021	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	37	5/17/2021	NON-COMPETING CONTINUATION	-$104,550
														Subtotal = $529,803

Issue Date FY: 2020 ( Subtotal = $548,263 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	38	4/10/2020	COMPETING CONTINUATION	$548,263
														Subtotal = $548,263

Issue Date FY: 2019 ( Subtotal = $474,202 )
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	37	5/10/2019	NON-COMPETING CONTINUATION	$474,202
														Subtotal = $474,202

Issue Date FY: 2018 ( Subtotal = $578,814 )
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	36	8/21/2018	SUPPLEMENT FOR EXPANSION	$100,100
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST., RM 479 572 UCB	BOULDER	CO	80303	BOULDER	USA	Biomedical Research and Research Training	000	36	5/15/2018	NON-COMPETING CONTINUATION	$478,714
														Subtotal = $578,814

Issue Date FY: 2017 ( Subtotal = $519,380 )
2017	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST., RM 479 572 UCB	BOULDER	CO	80303	BOULDER	USA	Biomedical Research and Research Training	003	35	6/6/2017	NON-COMPETING CONTINUATION	$478,714
2017	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST., RM 479 572 UCB	BOULDER	CO	80303	BOULDER	USA	Biomedical Research and Research Training	000	34	11/30/2016	SUPPLEMENT FOR EXPANSION	$40,666
2017	2016	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST., RM 479 572 UCB	BOULDER	CO	80303	BOULDER	USA	Biomedical Research and Research Training	002	34	1/21/2017	COMPETING CONTINUATION	$7,553
2017	2015	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST., RM 479 572 UCB	BOULDER	CO	80303	BOULDER	USA	Biomedical Research and Research Training	001	33	1/21/2017	NON-COMPETING CONTINUATION	-$7,553
														Subtotal = $519,380

Issue Date FY: 2016 ( Subtotal = $498,723 )
2016	2016	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	34	4/29/2016	COMPETING CONTINUATION	$498,723
														Subtotal = $498,723

Issue Date FY: 2015 ( Subtotal = $455,620 )
2015	2015	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	33	7/21/2015	NON-COMPETING CONTINUATION	$455,620
														Subtotal = $455,620

Issue Date FY: 2014 ( Subtotal = $534,134 )
2014	2014	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	31	12/11/2013	SUPPLEMENT FOR EXPANSION	$35,373
2014	2014	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	32	6/2/2014	NON-COMPETING CONTINUATION	$498,761
														Subtotal = $534,134

Issue Date FY: 2013 ( Subtotal = $499,351 )
2013	2013	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	31	6/12/2013	NON-COMPETING CONTINUATION	$499,351
														Subtotal = $499,351

Issue Date FY: 2012 ( Subtotal = $520,115 )
2012	2012	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	003	30	8/27/2012	SUPPLEMENT FOR EXPANSION	$80,345
2012	2012	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	002	30	5/24/2012	COMPETING CONTINUATION	$439,770
2012	2011	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	29	5/22/2012	SUPPLEMENT FOR EXPANSION	$0
2012	2010	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	29	5/22/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $520,115

Issue Date FY: 2011 ( Subtotal = $144,292 )
2011	2011	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	29	7/15/2011	SUPPLEMENT FOR EXPANSION	$144,292
2011	2010	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	29	7/14/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $144,292

Issue Date FY: 2010 ( Subtotal = $432,877 )
2010	2010	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	29	5/19/2010	NON-COMPETING CONTINUATION	$432,877
														Subtotal = $432,877

Issue Date FY: 2009 ( Subtotal = $430,737 )
2009	2009	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	001	28	7/28/2009	NON-COMPETING CONTINUATION	$430,737
2009	2008	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Biomedical Research and Research Training	000	27	8/4/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $430,737

Issue Date FY: 2008 ( Subtotal = $400,318 ) (Continued on the next page)
Grand Total All Awards = $12,406,657

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Myosin Gene Diversity and Function

Award Number: R01GM029090

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/1981

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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