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-F(1)F(o) complex. We tested the hypothesis that coupling factor 6 attenuates physiological cardiac hypertrophy induced by exercise and its benefit in mice.


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 ± 0.1 mm, 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.


CONCLUSIONS
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.
Department of Cardiology, Hirosaki University Graduate School of Medicine, 5-Zaifu-Cho, Hirosaki, Japan.
Shigeki
S
Sagara
Tomohiro
T
Osanai
Taihei
T
Itoh
Kei
K
Izumiyama
Shuji
S
Shibutani
Kenji
K
Hanada
Hiroaki
H
Yokoyama
Yuko
Y
Yamamoto
Takashi
T
Yokota
Hirofumi
H
Tomita
Koji
K
Magota
Ken
K
Okumura
D000222:Adaptation, Physiological; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015870:Gene Expression; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D010086:Oxidative Phosphorylation Coupling Factors / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins; D005082:Physical Exertion; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction; D013550:Swimming; D054088:Ventricular Septum / Q000187:drug effects / Q000473:pathology
D010086:Oxidative Phosphorylation Coupling Factors; D010750:Phosphoproteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; C000628217:F(6) ATPase; D025261:Mitochondrial Proton-Translocating ATPases