Kw. Saupe et al., IMPAIRED CARDIAC ENERGETICS IN MICE LACKING MUSCLE-SPECIFIC ISOENZYMES OF CREATINE-KINASE, Circulation research, 82(8), 1998, pp. 898-907
Our purpose was to determine whether hearts from mice bioengineered to
lack either the M isoform of creatine kinase (MCK-/- mice) or both th
e M and mitochondrial isoforms (M/MtCK(-/-) mice) have deficits in car
diac contractile function and energetics, which have previously been r
eported in skeletal muscle from these mice. The phenotype of hearts wi
th deleted creatine kinase (CK) genes is of clinical interest, since h
eart failure is associated with decreased total CK activity and change
s in the relative amounts of the CK isoforms in the heart. We measured
isovolumic contractile performance in isolated perfused hearts from w
ild-type, MCK-/-, and M/MtCK(-/-) mice simultaneously with cardiac ene
rgetics (P-31-nuclear magnetic resonance spectroscopy) at baseline, du
ring increased cardiac work, and during recovery. Hearts from wild-typ
e, MCK-/-, and M/MtCK(-/-) mice had comparable baseline function and r
esponded to 10 minutes of increased heart rate and perfusate Ca2+ with
similar increases in rate-pressure product (48+/-5%, 42+/-6%, and 51/-6%, respectively). Despite a similar contractile response, M/MtCK(-/
-) hearts increased [ADP] by 95%, whereas wild-type and MCK-/- hearts
maintained [ADP] at baseline levels. The free energy released from ATP
hydrolysis decreased by 3.6 kJ/mol in M/MtCK(-/-) hearts during incre
ased cardiac work but only slightly in wild-type (1.7 kJ/mol) and MCK-
/-(1.5 kJ/mol) hearts, in contrast to what has been reported in skelet
al muscle, M/MtCK(-/-) hearts were able to hydrolyze and resynthesize
phosphocreatine. Taken together, our results demonstrate that when CK
activity is lowered below a certain level, increases in cardiac work b
ecome more ''energetically costly'' in terms of high-energy phosphate
use, accumulation of ADP, and decreases in free energy released from A
TP hydrolysis, but not in terms of myocardial oxygen consumption.