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Functions of skeletal muscle mineralocorticoid receptor signaling in chronic and acute injury

Award Number: R01AR072574
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: 04/01/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Functions of skeletal muscle mineralocorticoid receptor signaling in chronic and acute injury - PROJECT SUMMARY Mineralocorticoid receptor (MR) antagonists (MRAs) have long been considered as anti-fibrotic drugs for treatment of heart failure. Although MRAs also have therapeutic benefits on skeletal muscle pathology in mouse models of Duchenne muscular dystrophy (DMD), their effects on skeletal muscle fibroblasts have never been defined. Fibroblasts produce extracellular matrix proteins that constitute fibrosis that replaces muscle tissue that leads to loss of ambulation, respiratory insufficiency and cardiomyopathy in DMD. Both MRAs and genetic deletion of MR in myofibers lead to reduced fibrosis in dystrophic models. In contrast, deletion of MR from myeloid cells increases fibrosis in dystrophic muscles. These data support the overall hypothesis that MR signaling has complex cross-talk between cell types in the injured muscle microenvironment that ultimately regulates fibrosis. The endogenous MR agonist aldosterone increases proliferation and migration of cardiac and renal fibroblasts, which is prevented by MRAs. Recent data support that fibroblasts differ between organs, preventing extrapolating conclusions from one tissue to another. In addition to its role in disease, fibrosis is essential for homeostasis of organ structure and wound healing. MRAs reduce the kinetics of acute injury repair in normal muscle, supporting a normal role for MR signaling in skeletal muscle wound healing. In this application, we will identify fibroblast regulation through non-fibroblast MR signaling and directly through fibroblast MR signaling in muscle wound healing and muscular dystrophy. We will compare molecular signatures, proliferation, migration, and activity between fibroblasts isolated from dystrophic mice treated with MRAs or untreated. We will compare these mechanisms in more fibrotic dystrophic diaphragm with less fibrotic limb muscles. To define mechanisms of MR signaling in essential fibrosis during wound healing versus chronic fibrosis during disease, we will compare fibroblasts isolated from mice with myofiber and myeloid MR knockouts in dystrophic muscles and in acutely injured wild-type muscles. Single-cell RNA-sequencing will be used to identify MRA effects on mononuclear cell populations in acute injury versus dystrophy. We will perform co-culture and conditioned media experiments with MR knockout and control myeloid cells or myotubes with fibroblasts to identify MR-regulated cross talk between these cell types. Direct MR signaling in skeletal muscle fibroblasts, different signaling in resolving fibrosis in wound healing versus chronic fibrosis in dystrophy, between dystrophic muscles with different fibrosis levels, or between young and old muscles have never been studied. Fibroblasts isolated from young and old mdx diaphragms and limb muscles and acutely-injured wild- type muscles will be treated with increasing dosages of aldosterone with or without an MRA and gene expression, proliferation, migration and activity will be compared. A fibroblast specific MR knockout will be generated for in vivo validation. These studies will define direct and indirect effects of MRAs on muscle fibroblasts to optimize MR modulation for DMD, other muscle diseases and possibly for acute muscle injuries.


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 = $435,618 )
2025	2025	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	7	8/22/2025	NON-COMPETING CONTINUATION	$435,618
2025	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	3/7/2025	COMPETING CONTINUATION	$42
2025	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/7/2025	NON-COMPETING CONTINUATION	-$42
														Subtotal = $435,618

Issue Date FY: 2024 ( Subtotal = $467,592 )
2024	2024	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	8/21/2024	COMPETING CONTINUATION	$467,592
2024	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $467,592

Issue Date FY: 2022 ( Subtotal = $367,064 )
2022	2022	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/29/2022	NON-COMPETING CONTINUATION	$367,064
														Subtotal = $367,064

Issue Date FY: 2021 ( Subtotal = $396,657 )
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	5/18/2021	NON-COMPETING CONTINUATION	$28,623
2021	2021	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	3/5/2021	NON-COMPETING CONTINUATION	$368,034
														Subtotal = $396,657

Issue Date FY: 2020 ( Subtotal = $404,388 )
2020	2020	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	4/13/2020	NON-COMPETING CONTINUATION	$404,388
														Subtotal = $404,388

Issue Date FY: 2019 ( Subtotal = $398,576 )
2019	2019	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/6/2019	NON-COMPETING CONTINUATION	$398,576
														Subtotal = $398,576

Issue Date FY: 2018 ( Subtotal = $374,719 )
2018	2018	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/20/2018	NEW	$374,719
														Subtotal = $374,719

Grand Total All Awards = $2,844,614

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Functions of skeletal muscle mineralocorticoid receptor signaling in chronic and acute injury

Award Number: R01AR072574

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: 04/01/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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