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-gamma coactivator-1 alpha (PGC-1 alpha) 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 alpha 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 Vo(2) [>14 versus <= 14 mL O-2.kg(-1).min(-1)]) and ventilatory efficiency (VE/Vco(2) 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 alpha (9.9 +/- 5.9 versus 4.5 +/- 1.9, P<0.01) gene expressions were greater in the high-peak Vo(2) group; correlation between FNDC5 and PGC-1 alpha was significant (r=0.56, P<0.05) only in the high-peak Vo(2) group. Similarly, FNDC5 and PGC-1 alpha gene expression was greater in the high-performance group based on lower VE/Vco(2) 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 alpha (r=0.55, P<0.05) only in the low VE/Vco(2) 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. (Circ Heart Fail. 2012;5:812-818.)