Date on Master's Thesis/Doctoral Dissertation

12-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Degree Program

Physiology and Biophysics, PhD

Committee Chair

Baba, Shahid

Committee Co-Chair (if applicable)

Bhatnagar, Aruni

Committee Member

Metz, Cynthia

Committee Member

Brainard, Robert Eli

Committee Member

Jones, Steven P.

Committee Member

Carll, Alex P.

Author's Keywords

Heart failure; muscle atrophy; ubiquitination; oxidative stress; carnosine; histidyl dipeptides; anserine

Abstract

Introduction: Heart failure is a systemic disease associated with multiple comorbidities, such as skeletal muscle wasting and cardiopulmonary disease. Muscle wasting in heart failure patients is a severe comorbidity associated with decreased exercise capacity and poor quality of life. Previous reports show that oxidative stress is increased in the skeletal muscle of heart failure patients, which can directly lead to muscle wasting. However, antioxidant intervention in these patients was unable to improve cardiac function and consequently had no effect on muscle wasting. Although oxidative stress is the primary driver of skeletal muscle atrophy, no attempt has been made to examine whether the downstream effectors of oxidative stress, toxic lipid peroxidation products, such as 4-hydroxynonenal and acrolein, could contribute to heart failure-induced muscle wasting. These toxic aldehydes bind with proteins, forming aldehyde-modified protein adducts, which could activate autophagy and endoplasmic reticulum (ER) stress, known to promote muscle atrophy. In the cells, there is an elaborate defense mechanism to remove these toxic aldehydes via enzymatic and

nucleophilic defense, such as glutathione and carnosine (-alanine-histidine), synthesized by the enzyme carnosine synthase (Carns). Among all these defense mechanisms, only carnosine levels can be altered by feeding and thus could serve as a readily available tool for translation in human patients. Hypothesis: Carnosine by removing toxic aldehydes from the skeletal muscle could preserve muscle mass and function during heart failure. Methods: Wild-type (WT) and muscle-specific CARNS transgenic (Tg) mice were subjected to sham and transverse aortic constriction (TAC) surgeries. Cardiac function, muscle strength, atrophic and inflammatory markers, aldehyde modified protein, CARNS, and histidyl dipeptides were measured after 12 weeks. Results: In the setting of heart failure, reduced carnosine availability exacerbates oxidative stress, impairs metabolic flexibility, and accelerates muscle wasting, thereby aggravating exercise intolerance. To investigate the protective effects of carnosine, we investigated skeletal muscle-specific overexpression of carnosine synthase, which significantly elevated carnosine content in muscle. This intervention preserves muscle mass, improves muscle function, and enhances endurance capacity in heart failure mice by mitigating oxidative stress. Interestingly, female heart failure mice displayed resistance to skeletal muscle atrophy, suggesting sex-specific differences in disease progression and adaptive mechanisms. Conclusion: These findings highlight carnosine metabolism as a novel therapeutic target to combat skeletal muscle atrophy and exercise intolerance in heart failure, while also highlighting the need to investigate sex-related differences in muscle adaptation.

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