Neladenoson, a partial adenosine A1-receptor agonist, improves mitochondrial function in skeletal muscle of dogs with chronic heart failure

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Conference Proceeding

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Eur J Heart Fail


Background: Exercise intolerance (Ex-Int) is a feature ofchronic heart failure (HF) and in particular, HF withpreserved ejection fraction (HFpEF) and attributable, in part, to skeletal muscle (SM) abnormalities of fiber type composition and mitochondrial (MITO) dysfunction. Inpatients and dogs with HF, SM aerobic, MITO-dependent, type-I fibers decrease in number while anaerobic type-II fibers increase; a maladaptation that contributes to Ex-Int. We previously showed that chronic therapy withcapadenoson, a partial adenosine A1-receptor agonist (pA1RA), improves LV function in HF dogs and therapy withneladenoson (NELA), a novel pA1RA, normalizes MITO function in failing cardiomyocytes. This study examined the effects of NELA on MITO function in SM biopsies from normal (NL) dogs and dogs with microembolization-induced HF. Methods: Fresh SM open biopsies (6 grams) were obtained from the hind leg Vastus Lateralis muscle of 6 NL and 6 HF anesthetized dogs. Samples were cut into thin sections, divided into 4 equal portions, and one portion each incubated in 0 (vehicle), 3, 10, and 30 nM concentration of NELA respectively for one hour at 37°C. At end of incubation, MITO were isolated from SM and their function assessed. MITO ADP-stimulated state-3 respiration (ADPresp) was measured using a Strathklein respirometer, MITO complex-IV (COX-IV) activity was measured polarographically and MITO maximum rate of ATP synthesis (ATPsyn) was measured using the bioluminescent ApoSENSOR assay kit. Results: Increasing concentration ofNELA had no effect onmeasures ofMITO function in SM from NL dogs (Table). In SM from HF dogs, depressed levels of MITO ADPresp, ATPsyn, and COX-IV activity increased significantly in a dose-dependent manner after exposure to NELA (Table). Conclusions: The results indicate that NELA improves MITO function of SM of dogs with HF. These improvements can potentially reduce/reverse Ex-Int in HF. (Table Presented).



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