Friday, July 4, 2025 7/4/2025

MuRF1 substrates and mechanisms of skeletal muscle atrophy

Award Number: R21AR084235
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: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2026

Group Awards By:

View Award Description

MuRF1 substrates and mechanisms of skeletal muscle atrophy - SUMMARY Skeletal muscle atrophy continues to be a serious consequence of many diseases and conditions for which there is no effective treatment. The E3 ubiquitin ligase, MuRF1 (Trim63), is selectively expressed in striated muscle and has been shown to be elevated in a myriad of atrophy-inducing conditions in both rodent and human muscle and thus is routinely used as a marker of muscle atrophy. Given that MuRF1 is associated with multiple forms of atrophy, and deletion can lead to partial muscle sparing, MuRF1 has been considered a strong candidate for drug development for the treatment of muscle atrophy. However, targeting specific E3 ligases has been difficult to achieve and thus a greater understanding of the downstream targets of MuRF1 could identify new targets for drug development. We have recently shown that overexpression of a full length MuRF1 plasmid into multiple hindlimb muscles of the mouse using in vivo electroporation induces significant atrophy of muscle fibers by 14 days. In an initial discovery effort, we used unbiased ubiquitin modification site-mapping (di-glycine (di-Gly) remnants proteomics followed by liquid chromatography and tandem mass spectrometry and identified 169 lysine sites on 56 proteins that were differentially ubiquitinated in response to MuRF1 overexpression in skeletal muscle. The list of putative MuRF1 substrates includes many proteins not previously linked to MuRF1. Further, many of the putative MuRF1 substrates were ubiquitinated on a single lysine residue and were not immediately targeted for degradation. Our recent data challenges the deeply entrenched dogma that thick filament proteins are the sole targets of MuRF1 and that the role of MuRF1-mediated ubiquitylation is solely protein degradation. The overall objective of the current proposal is to determine the mechanisms by which MuRF1 induces muscle atrophy. We will use diGly remnant affinity proteomics and deuterium oxide labeling in wild type and MuRF1 knock out mice at rest and following a time-course of denervation to test the hypothesis that upregulation of MuRF1 results in the disassembly of the sarcomere through targeted ubiquitylation of specific proteins resulting in increased turnover of the myofibrillar proteins and a loss of fiber cross-sectional area and muscle atrophy. Further, we hypothesize that ubiquitylation of myofibrillar proteins occurs in a stepwise manner with ubiquitylation by MuRF1 being a priming step for further ubiquitylation by other E3 ligases. The deliverables from this investigation will likely generate a paradigm shift in our understanding of how MuRF1 regulates muscle atrophy and may lead to the identification of new therapeutic targets for the treatment and prevention of muscle wasting.


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 = $181,924 )
2025	2025	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	3/3/2025	NON-COMPETING CONTINUATION	$168,795
2025	2025	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	4/29/2025	NON-COMPETING CONTINUATION	$13,129
														Subtotal = $181,924

Issue Date FY: 2024 ( Subtotal = $225,060 )
2024	2024	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/27/2024	NEW	$225,060
														Subtotal = $225,060

Grand Total All Awards = $406,984

Top

All Categories

About

Search

Reports

Data Submission

Award Information

MuRF1 substrates and mechanisms of skeletal muscle atrophy

Award Number: R21AR084235

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: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer