Expression of the Irisin Precursor FNDC5 in Skeletal Muscle Correlates With Aerobic Exercise Performance in Patients With Heart Failure

Background—Exercise-induced increase in peroxisome proliferator-activated receptor-&ggr; coactivator-1&agr; (PGC-1&agr;) expression has been shown to increase the expression of the fibronectin type III domain containing 5 (FNDC5) gene and thereby its product, irisin, in mice. Given that exercise intolerance is a hallmark characteristic of heart failure (HF), and because PGC-1&agr; and irisin promote exercise benefits in animals, we hypothesized that expression of these genes relates to aerobic performance in patients with HF. Methods and Results—Systolic HF (left ventricular ejection fraction ⩽40%) patients underwent cardiopulmonary exercise testing to evaluate aerobic performance. High versus low aerobic performance was assessed using oxygen consumption (peak VO2 [>14 versus ⩽14 mL O2·kg−1·min−1]) and ventilatory efficiency (VE/VCO2 slope [<34 versus ≥34]). Muscle biopsies of the vastus lateralis and real-time polymerase chain reaction were used to quantify muscle gene expression. Twenty-four patients were studied. FNDC5 (5.7±3.5 versus 3.1±1.2, P<0.05) and PGC-1&agr; (9.9±5.9 versus 4.5±1.9, P<0.01) gene expressions were greater in the high-peak VO2 group; correlation between FNDC5 and PGC-1&agr; was significant (r=0.56, P<0.05) only in the high-peak VO2 group. Similarly, FNDC5 and PGC-1&agr; gene expression was greater in the high-performance group based on lower VE/VCO2 slopes (5.8±3.6 versus 3.3±1.4, P<0.05 and 9.7±6 versus 5.3±3.4, P<0.05); FNDC5 also correlated with PGC-1&agr; (r=0.55, P<0.05) only in the low VE/VCO2 slope group. Conclusions—This is the first study to show that FNDC5 expression relates to functional capacity in a human HF population. Lower FNDC5 expression may underlie reduced aerobic performance in HF patients.