Abstract 4134449: Increasing Histidyl dipeptides in Skeletal Muscle Preserves Muscle Mass and Function During Heart Failure.

Background: In heart failure patients muscle wasting is a serious comorbidity. Oxidative stress and inflammatory cytokines, which cause muscle wasting, are increased in the skeletal muscle of heart failure patients. Oxidative stress leads to oxidation of lipids, generating toxic lipid peroxidation products, such as acrolein, which activates TNFa. Whether lipid peroxidation products accumulate in muscle and their removal from muscle influences muscle atrophy during heart failure has not been studied. In the muscle there are histidyl dipeptides, such as carnosine, ranging between 5-10 mM, synthesized via enzyme carnosine synthase (CARNS) that bind lipid peroxidation products. We examined whether intramuscular histidyl dipeptides influences heart failure-induced muscle wasting. Hypothesis: Histidyl dipeptides, alleviates intramuscular inflammation, preserves 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 heart failure mice, weight of gastrocnemius (sham: 18.64 ± 1.73 vs TAC: 14.10 ± 0.90 mg, p=0.005), soleus (sham: 6.06 ± 0.82 vs TAC: 4.14 ± 0.70 mg, p=0.001), and tibialis anterior (sham:10.76 ± 1.62 vs TAC: 6.22 ± 1.83 mg, p=0.003), were decreased. Muscle strength was diminished (sham: 2.81 ± 0.36 vs TAC: 1.52 ± 0.27 N, p=0.004). Atrophic marker, atrogin1, aldehyde protein adducts and TNF-a were increased in the gastrocnemius muscle of TAC mice (~2-3-fold vs sham, p<0.05). CARNS expression and carnosine was decreased in different muscles of TAC mice (gastrocnemius; sham: 43.38 ± 20.46 vs TAC: 24.48 ± 6.49 nmoles/mg protein, p=0.03; soleus; sham: 22.04 ± 11.36 vs TAC: 11.02 ± 4.69 nmoles/mg protein, p=0.03; and tibialis; sham: 27.9 ± 11.70 vs TAC: 15.50 ± 3.48 nmoles/mg protein, p=0.01). Gastrocnemius muscle weight (WT TAC: 14.38 ± 1.08 vs Tg TAC: 17.30 ± 1.32 mg, p=0.004) and muscle strength (WT TAC: 3.06 ± 0.32 vs Tg TAC: 3.98 ± 0.41 N) were preserved, atrogin and TNFa expressions were decreased in gastrocnemius muscle of Tg TAC mice (~2-3-fold, p=0.04). Conclusion: Increasing intramuscular histidyl dipeptides alleviates muscle inflammation, preserves muscle mass, and function during heart failure.