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Defining the relationship between titin segment A168-170 and the E3 ligase MuRF1 in skeletal muscle atrophy

Award Number: F31AR085369
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/14/2025
PERIOD OF PERFORMANCE END DATE: 08/13/2028

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Defining the relationship between titin segment A168-170 and the E3 ligase MuRF1 in skeletal muscle atrophy - Abstract Skeletal muscle plasticity is highly dependent on load, and muscles quickly atrophy under many conditions including disuse, systemic disease, aging, etc., causing drastic consequences for quality of life. Muscle wasting and weakness is caused by disassembly of the sarcomere, the basic contractile structure of muscle. The myofilament titin contains spring-like regions and multiple sites for signaling protein binding, making it a sentinel for changes in muscle load. Titin’s A-band to M-line transition contains an E3 ligase binding site (domains A168-170) adjacent to its mechanosensitive pseudokinase domain (TK). E3 ligases ubiquitinate proteins to target them for degradation, making them important members of the muscle atrophy program. The E3 ligase MuRF1 (TRIM63) is termed an “atrogene” for its propensity to be upregulated in the early stages of muscle atrophy. In vivo overexpression of MuRF1 in the absence of unloading causes muscle wasting at the muscle weight and fiber CSA levels. In vitro experiments have shown that overexpressed MuRF1 colocalizes with the A168-TK segment and causes loss of M-line and thick filament structure. Furthermore, in vitro and in vivo studies show that MuRF1 heavily ubiquitinates titin during atrophy, such that titin is MuRF1’s most highly ubiquitinated substrate. Myomesin and myosin heavy chain are also ubiquitinated by MuRF1, and several thick filament protein components are degraded in a MuRF1-dependent manner during atrophy. The overall goal of this proposal is to decipher the role of titin segment A168-170 and MuRF1 during muscle atrophy, and my overarching hypothesis is that the interaction of MuRF1 and titin A168-170 is important for initiating atrophy by promoting M-line and thick filament disassembly. Toward this end, I generated a mouse model, TtnA168-170→I104-106, in which titin’s E3-binding domains A168-170 are “substituted” with three titin domains lacking an E3 binding site, I104-106. I opted for this novel “substitution” model to preserve general titin structure while preventing MuRF1 (and other E3s) from binding. My preliminary data indicates that titin incorporation and expression are preserved in this mouse model, but that localization of overexpressed MuRF1 at the M-line is lost. To test my hypothesis, I will subject control (WT) and TtnA168-170→I104-106 “substitution” mice to two atrophy models: 1) MuRF1 overexpression via AAV9: CMV-MuRF1-Spot tag, and 2) sciatic nerve transection. I will critically analyze the response of both genotypes based on ubiquitin remnant-enriched quantitative proteomics, muscle structural features, and levels of autophagy- and proteasome-linked proteins and myofilament proteins in fractionated (sarcoplasmic vs. myofibrillar) muscle. Upon completion of this project, I will have established the role of the interaction between titin A168-170 and MuRF1 in initiating sarcomere disassembly during atrophy states, which will indicate if the titin-MuRF1 interaction is a viable therapeutic target.


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: 2026 ( Subtotal = $50,114 )
2026	2026	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/6/2026	NON-COMPETING CONTINUATION	$50,114
														Subtotal = $50,114

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	8/20/2025	NEW	$0
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/14/2025	NEW	$49,538
														Subtotal = $49,538

Grand Total All Awards = $99,652

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Defining the relationship between titin segment A168-170 and the E3 ligase MuRF1 in skeletal muscle atrophy

Award Number: F31AR085369

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/14/2025

PERIOD OF PERFORMANCE END DATE: 08/13/2028

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