Abstract Body (Do not enter title and authors here): Background: Exercise intolerance is a cardinal symptom of heart failure contributing to poor quality of life and increased mortality. Extensive evidence shows skeletal muscle abnormalities underlie exercise intolerance in heart failure; however the pathophysiological mechanisms are not completely understood. Our previous report showed that in WT C57BL/6J mice transverse aortic constriction (TAC) reduces histidyl dipeptides in skeletal muscle and grip strength. Histidyl dipeptides, such as carnosine, in muscle has the abilities to bind with toxic lipid peroxidation products and buffer intracellular pH. Carnosine is synthesized via the enzyme carnosine synthase (Carns). The impact of decrease in skeletal muscle histidyl dipeptides observed in the context of heart failure conditions on exercise capacity has not been studied.
Hypothesis: Reduced skeletal muscle carnosine during heart failure diminishes exercise capacity and exacerbates muscle atrophy.
Methods: Skeletal muscle specific Carns-knock out mice (M-Carns^-/-) were generated by breeding Carns^fl/fl with HSA-Cre mice. MCarns^-/- were fed with carnosine (15g/L carnosine) in water for 4 wks to replenish carnosine and examine the effect on muscle function. Muscle strength, voluntary wheel running and exercise capacity were measured by grip strength meter, voluntary wheels and treadmill respectively.
Results: Compared with Carns^fl/fl mice, M-Carns^-/- mice exhibited significantly decreased carnosine levels (MCarns^-/-:0.12±0.03vs Carns^fl/fl:6.06±2.07 nmoles/mg tissue). Decrease in endogenous production of SKM carnosine was associated with decrease in gastrocnemius muscle weight (MCarns^-/-:12.22±1.09vsCarns^fl/fl:14.92±0.69mg, p=0.001). Muscle function was significantly impaired in M-Carns^-/- mice, muscle strength (M-Carns^-/-: 3.39±0.43 vsCarns^fl/fl:4.65±0.23N,p=0.005), voluntary wheel running distance (MCarns^-/-:4211±698vs Carns^fl/fl: 7513.±105.91m, p=0.006), running distance (MCarns^-/-:123.85±37.94vsCarns^fl/fl:227±46.53m/min,p=0.002). Notably, carnosine feeding significantly restored grip strength in MCarns^-/- mice (MCarns^-/-+car:4.31±0.25 vs Carns^fl/fl:4.39±0.22 N, p=0.7 and running capacity (MCarns^-/-+car:205.56±0.09, p=0.06, Carns^fl/fl:266.43±84.16, p=0.26)
Conclusion: Our findings suggest, carnosine is essential for preserving muscle function. Enhancing histidyl dipeptide synthesis in skeletal muscle may offer a promising therapeutic strategy to improve exercise capacity and preserve muscle mass in HF.