Overexpression of coupling factor 6 attenuates exercise-induced physiological cardiac hypertrophy by inhibiting PI3K/Akt signaling in mice

Background: Regular exercise improves systolic cardiac dysfunction through Akt cascade-mediated physiological hypertrophy in congestive heart failure. Tissue acidosis impairs Akt cascade, and coupling factor 6 induces tissue acidosis via activation of ecto-F1Fo complex. We tested the hypothesis that coupling factor 6 attenuates physiological cardiac hypertrophy induced by exercise and its benefit in mice. Methods and results: Adult wild-type mice (n = 20) and coupling factor 6-overexpressing transgenic mice (n = 20) were divided into two groups with or without 4-week exercise consisting of 90-min swimming twice daily. Left ventricular posterior wall and interventricular septum thicknesses were increased by 0.12 +/- 0.1 and 0.16 +/- 0.1mm, respectively, after 4-week swimming in wild-type mice (both P < 0.01), but unchanged in transgenic mice. Fractional shortening was increased from 37 +/- 1 to 41 +/- 1% after 4-week swimming in wild-type mice (P < 0.05), whereas it was unchanged in transgenic. The insulin-like growth factor 1 (IGF-1) receptor protein and its phosphorylated form in the heart were both increased by 1.83 +/- 0.23 and 1.83 +/- 0.09 times, respectively, after 4-week swimming in wild-type mice (both P < 0.05), but were unchanged in transgenic. Downstream phosphoinsulin receptor substrate 1, phosphoinositide 3-kinase, and phospho-Akt were increased by 2.22 +/- 0.22, 1.78 +/- 0.31, and 2.24 +/- 0.49 times, respectively, in wild-type mice (all P < 0.05), but were unchanged in transgenic. Restoration of phospho-Akt by IGF-1 injection recovered left ventricular hypertrophy and systolic function after 4-week swimming in transgenic. Conclusion: Overexpression of coupling factor 6 attenuates exercise-induced physiological cardiac hypertrophy by downregulating Akt signaling, thereby cancelling its benefit for cardiac function in mice. Reduction in coupling factor 6 level seems to be useful for drawing the exercising effects on cardiac function.