Wednesday, April 2, 2025 4/2/2025

Costamere Defects in Muscular Dystrophies

Award Number: R01AR049899
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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Costamere Defects in Muscular Dystrophies - PROJECT SUMMARY/ABSTRACT While abundant skeletal (ask-actin) and cardiac (aca-actin) actin isoforms are famous for their essential role in striated muscle contraction, low abundance non-muscle “cytoplasmic” actin isoforms (bcyto- and gcyto-actin) are also emerging as important in the maintenance of specialized structures (and functions) in normal and diseased skeletal muscle. During this project, we generated and characterized muscle-specific mouse lines either lacking or overexpressing bcyto-actin or gcyto-actin to understand their endogenous functions and role(s) in dystrophin-deficient muscular dystrophy. Interestingly, each bcyto-actin or gcyto-actin single knockout develops a qualitatively similar phenotype characterized by a progressive myopathy with significant myofiber degeneration/regeneration and muscle weakness. We have shown that skeletal muscle-specific overexpression of bcyto-actin or gcyto-actin in dystrophin-deficient mdx mice affords significant protection from eccentric contraction-induced force drop while overexpression of a C272A mutant of gcyto-actin affords no protection. These and other data suggest that eccentric contraction drives a rapidly-reversible, reactive oxygen species (ROS)-mediated inhibition of sarcomeric contractility that may function to protect dystrophic muscles from damage caused by repeated, high force contractions. Our new preliminary data show that muscle-specific ablation of bcyto-actin or gcyto-actin from wildtype muscle results in eccentric contraction-induced force drop that is reversed by the nonspecific antioxidant N-acetylcysteine. Finally, we have obtained new data suggesting that gcyto-actin is important for repair of membrane damage. Going forward, we will make use of our unique animal models, isoform-specific reagents, and biochemical and physiological methodologies to address new fundamental questions about cytoplasmic actins in normal skeletal muscle function and in dystrophin-deficient muscular dystrophy. In aim 1, we will identify the sources of ROS contributing to eccentric contraction-induced force drop in dystrophic mdx skeletal muscle as well as the downstream targets of ROS that ultimately inhibit force production. In aim 2, we will investigate the role of oxidative stress in driving the myopathy and eccentric contraction-induced force drop associated with genetic ablation of bcyto- or gcyto-actin in skeletal muscle. In aim 3, the interplay between cytoplasmic actin isoforms and ROS in membrane repair will be investigated using state-of-the-art imaging approaches to analyze muscles from the same mouse lines used in aims 1 and 2. The results of the proposed studies will further delineate the unique and important contributions of cytoplasmic actin isoforms to the function of normal and dystrophic skeletal muscle.


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 = $528,158 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	21	2/19/2025	NON-COMPETING CONTINUATION	$528,158
														Subtotal = $528,158

Issue Date FY: 2024 ( Subtotal = $569,235 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	20	3/4/2024	NON-COMPETING CONTINUATION	$528,158
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	20	5/22/2024	NON-COMPETING CONTINUATION	$41,077
														Subtotal = $569,235

Issue Date FY: 2023 ( Subtotal = $586,841 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	19	3/3/2023	NON-COMPETING CONTINUATION	$586,841
														Subtotal = $586,841

Issue Date FY: 2022 ( Subtotal = $580,972 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	18	2/21/2022	NON-COMPETING CONTINUATION	$528,154
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	18	8/5/2022	NON-COMPETING CONTINUATION	$52,818
														Subtotal = $580,972

Issue Date FY: 2021 ( Subtotal = $599,579 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	17	2/26/2021	COMPETING CONTINUATION	$599,579
2021	2019	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	16	6/16/2021	NON-COMPETING CONTINUATION	$0
2021	2019	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	16	2/19/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $599,579

Issue Date FY: 2019 ( Subtotal = $378,195 )
2019	2019	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	16	3/23/2019	NON-COMPETING CONTINUATION	$378,195
														Subtotal = $378,195

Issue Date FY: 2018 ( Subtotal = $378,195 )
2018	2018	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	5/7/2018	NON-COMPETING CONTINUATION	$378,195
														Subtotal = $378,195

Issue Date FY: 2017 ( Subtotal = $378,195 )
2017	2017	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	14	6/14/2017	NON-COMPETING CONTINUATION	$37,820
2017	2017	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	14	4/7/2017	NON-COMPETING CONTINUATION	$340,375
														Subtotal = $378,195

Issue Date FY: 2016 ( Subtotal = $378,195 )
2016	2016	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	3/25/2016	NON-COMPETING CONTINUATION	$378,195
														Subtotal = $378,195

Issue Date FY: 2015 ( Subtotal = $378,195 )
2015	2015	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	12	4/2/2015	COMPETING CONTINUATION	$69,117
2015	2015	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	12	3/31/2015	COMPETING CONTINUATION	$309,078
2015	2014	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	3/30/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $378,195

Issue Date FY: 2014 ( Subtotal = $339,421 )
2014	2014	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	11	5/30/2014	NON-COMPETING CONTINUATION	$27,711
2014	2014	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	2/18/2014	NON-COMPETING CONTINUATION	$311,710
														Subtotal = $339,421

Issue Date FY: 2013 ( Subtotal = $329,028 )
2013	2013	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	5/28/2013	NON-COMPETING CONTINUATION	$329,028
														Subtotal = $329,028

Issue Date FY: 2012 ( Subtotal = $346,344 )
2012	2012	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	3/19/2012	NON-COMPETING CONTINUATION	$346,344
														Subtotal = $346,344

Issue Date FY: 2011 ( Subtotal = $346,344 )
2011	2011	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	8	6/24/2011	NON-COMPETING CONTINUATION	$22,041
2011	2011	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	1/19/2011	NON-COMPETING CONTINUATION	$324,303
														Subtotal = $346,344

Issue Date FY: 2010 ( Subtotal = $387,063 )
2010	2010	UNIVERSITY OF MINNESOTA, OFFICE OF STUDENT FINANCE AID	106 PLEASANT SE, 210 FRASER HL	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	7	4/14/2010	COMPETING CONTINUATION	$352,400
2010	2009	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	4/14/2010	NON-COMPETING CONTINUATION	$0
2010	2009	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	4/14/2010	NON-COMPETING CONTINUATION	$34,663
														Subtotal = $387,063

Issue Date FY: 2009 ( Subtotal = $346,634 )
2009	2009	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	6/8/2009	NON-COMPETING CONTINUATION	$34,663
2009	2009	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	11/24/2008	NON-COMPETING CONTINUATION	$311,971
														Subtotal = $346,634

Issue Date FY: 2008 ( Subtotal = $336,457 )
2008	2008	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	2/5/2008	NON-COMPETING CONTINUATION	$336,457
														Subtotal = $336,457

Issue Date FY: 2007 ( Subtotal = $333,234 )
2007	2007	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/29/2007	NON-COMPETING CONTINUATION	$333,234
														Subtotal = $333,234

Issue Date FY: 2006 ( Subtotal = $327,425 ) (Continued on the next page)
2006	2006	UNIVERSITY OF MINNESOTA	UNIV GATEWAY#450/200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/7/2006	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$265,609
Grand Total All Awards = $8,167,415

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Costamere Defects in Muscular Dystrophies

Award Number: R01AR049899

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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