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Mechanisms Regulating Muscle Stem Cell Homeostasis

Award Number: R01AR049446
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: 04/01/2005
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Mechanisms Regulating Muscle Stem Cell Homeostasis - Project Summary Skeletal muscle tissue is essential for life, requiring continuous maintenance and repair by a resident population of skeletal muscle stem cells or satellite cells (SCs). Maintenance and repair of skeletal muscle re- quires fusion of SCs into existing myofibers or fusion of SCs with each other to replace a damaged myofiber, as inhibiting SC fusion prevents hypertrophy of myofibers and elimination of SCs prevents skeletal muscle repair. Inactive SCs are mitotically quiescent, residing between the myofiber plasma membrane and the basement membrane, an inherently asymmetric environment. Following a muscle injury, quiescent SCs activate, exiting quiescence and proliferate, eventually terminally differentiating with daughter cells fusing or re-acquiring qui- escence and re-occupying their niche to replenish the SC population. Replenishment of SCs occurs via symmet- ric or asymmetric division, likely balanced by the extent of muscle repair or maintenance. Understanding the mechanisms regulating SC division will provide knowledge for development of therapeutics targeting SCs for improving muscle repair to combat aging and muscle diseases. Single cell sequencing and single nuclear se- quencing of skeletal muscle has revealed unexpected heterogeneity in skeletal muscle myonuclei as well as the unexpected contribution of non-SC progenitors to myonuclei. Because skeletal muscle cells are syncytial, de- rived from fusion of many hundreds of progenitors or SCs, lineage tracing the parental cells producing myonu- clei has proven highly technically challenging, broadening a knowledge gap that does not exist in tissues popu- lated by mononuclear cells. To fill this knowledge gap, we have developed a novel approach to lineage trace my- onuclear parents that is a flexible, quantitative method that can be applied to SCs and non-myogenic myonu- clear progenitors. Moreover, our method allows quantification of the cell divisions a myonucleus underwent prior to terminal differentiation, which has not previously been attempted in most lineage tracing experiments. We plan employ the methodology we have developed to aid in answering: (i) Are clonally diverse myonuclei derived from distinct progenitors?, (ii) Are heterogeneous populations of SCs responsible for producing myo- nuclei and SCs, respectively?, and, (iii) What environmental signals affect SC behavior during production of centrally located myonuclei vs. production of peripheral nuclei? to fulfill broad knowledge gaps in understand- ing how myonuclear diversity ensures that skeletal muscle is functional and healthy.


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 = $486,732 )
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	18	3/3/2025	NON-COMPETING CONTINUATION	$451,607
2025	2025	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	18	5/14/2025	NON-COMPETING CONTINUATION	$35,125
														Subtotal = $486,732

Issue Date FY: 2024 ( Subtotal = $486,732 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	17	6/12/2024	NON-COMPETING CONTINUATION	$35,125
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	17	3/19/2024	NON-COMPETING CONTINUATION	$451,607
														Subtotal = $486,732

Issue Date FY: 2023 ( Subtotal = $521,182 )
2023	2023	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	16	4/24/2023	COMPETING CONTINUATION	$85,394
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	16	4/19/2023	COMPETING CONTINUATION	$521,182
2023	2020	THE REGENTS OF THE UNIVERSITY OF COLORADO	3100 MARINE ST	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	15	4/24/2023	NON-COMPETING CONTINUATION	-$85,394
														Subtotal = $521,182

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	5/3/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $335,418 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	15	6/26/2020	NON-COMPETING CONTINUATION	$335,418
														Subtotal = $335,418

Issue Date FY: 2019 ( Subtotal = $335,548 )
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	14	6/26/2019	NON-COMPETING CONTINUATION	$335,548
														Subtotal = $335,548

Issue Date FY: 2018 ( Subtotal = $335,673 )
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST STE 481 572 UCB	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	13	7/6/2018	NON-COMPETING CONTINUATION	$335,673
														Subtotal = $335,673

Issue Date FY: 2017 ( Subtotal = $335,673 )
2017	2017	REGENTS OF THE UNIVERSITY OF COLORADO, THE	3100 MARINE ST., RM 479 572 UCB	BOULDER	CO	80303	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	12	7/21/2017	NON-COMPETING CONTINUATION	$335,673
														Subtotal = $335,673

Issue Date FY: 2016 ( Subtotal = $335,909 )
2016	2016	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	11	7/13/2016	COMPETING CONTINUATION	$335,909
														Subtotal = $335,909

Issue Date FY: 2015 ( Subtotal = $428,525 )
2015	2015	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	5/13/2015	NON-COMPETING CONTINUATION	$428,525
														Subtotal = $428,525

Issue Date FY: 2014 ( Subtotal = $394,721 )
2014	2014	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	7/9/2014	NON-COMPETING CONTINUATION	$336,263
2014	2014	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	9	8/22/2014	SUPPLEMENT FOR EXPANSION	$58,458
														Subtotal = $394,721

Issue Date FY: 2013 ( Subtotal = $325,969 )
2013	2013	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	5/22/2013	NON-COMPETING CONTINUATION	$325,969
														Subtotal = $325,969

Issue Date FY: 2012 ( Subtotal = $343,125 )
2012	2012	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	5/30/2012	NON-COMPETING CONTINUATION	$343,125
														Subtotal = $343,125

Issue Date FY: 2011 ( Subtotal = $343,125 )
2011	2011	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	7/8/2011	COMPETING CONTINUATION	$343,125
														Subtotal = $343,125

Issue Date FY: 2009 ( Subtotal = $457,319 )
2009	2009	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Trans-NIH Recovery Act Research Support	001	5	9/16/2009	SUPPLEMENT FOR EXPANSION	$157,297
2009	2009	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/23/2009	NON-COMPETING CONTINUATION	$300,022
														Subtotal = $457,319

Issue Date FY: 2008 ( Subtotal = $300,155 )
2008	2008	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	3/28/2008	NON-COMPETING CONTINUATION	$300,155
														Subtotal = $300,155

Issue Date FY: 2007 ( Subtotal = $306,413 )
2007	2007	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	3/30/2007	NON-COMPETING CONTINUATION	$306,413
														Subtotal = $306,413

Issue Date FY: 2006 ( Subtotal = $309,187 )
2006	2006	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/30/2006	NON-COMPETING CONTINUATION	$309,187
														Subtotal = $309,187

Issue Date FY: 2005 ( Subtotal = $309,796 )
2005	2005	UNIVERSITY OF COLORADO, OFFICE OF CONTRACTS & GRANTS	CAMPUS BOX B-19	BOULDER	CO	80309	BOULDER	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/28/2005	NEW	$309,796
														Subtotal = $309,796

Grand Total All Awards = $6,691,202

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Mechanisms Regulating Muscle Stem Cell Homeostasis

Award Number: R01AR049446

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: 04/01/2005

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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