Enhanced mitochondrial sensitivity to creatine in rats bred for high aerobic capacity

1 Physiology Division, Department of Medicine, University of California-San Diego, La Jolla; 2 Department of Kinesiology, California State University Northridge, Northridge, California; and 3 Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, Michigan Submitted 6 December 2005 ; accepted in final form 11 January 2006 Qualitative and quantitative measures of mitochondrial function were performed in rats selectively bred 15 generations for intrinsic aerobic high running capacity (HCR; n = 8) or low running capacity (LCR; n = 8). As estimated from a speed-ramped treadmill exercise test to exhaustion (15° slope; initial velocity of 10 m/min, increased 1 m/min every 2 min), HCR rats ran 10 times further (2,375 ± 80 m) compared with LCR rats (238 ± 12 m). Fiber bundles were obtained from the soleus and chemically permeabilized. Respiration was measured 1 ) in the absence of ADP, 2 ) in the presence of a submaximally stimulating concentration of ADP (0.1 mM ADP, with and without 20 mM creatine), and 3 ) in the presence of a maximally stimulating concentration of ADP (2 mM). Although non-ADP-stimulated and maximally ADP-stimulated rates of respiration were 13% higher in HCR compared with LCR, the difference was not statistically significant ( P > 0.05). Despite a similar rate of respiration in the presence of 0.1 mM ADP, HCR rats demonstrated a higher rate of respiration in the presence of 0.1 mM ADP + 20 mM creatine (HCR 33% higher vs. LCR, P < 0.05). Thus mitochondria from HCR rats exhibit enhanced mitochondrial sensitivity to creatine (i.e., the ability of creatine to decrease the K m for ADP). We propose that increased respiratory sensitivity to ADP in the presence of creatine can effectively increase muscle sensitivity to ADP during exercise (when creatine is increased) and may be, in part, a contributing factor for the increased running capacity in HCR rats. ADP; skeletal muscle; oxidative phosphorylation; exercise; high-capacity runners; low-capacity runners Address for reprint requests and other correspondence: B. Walsh, Univ. of California-San Diego, Dept. of Medicine, Physiology Div., 9500 Gilman Dr., MC0623A, La Jolla, CA 92093-0623 (e-mail: bjwalsh{at}ucsd.edu )