Breast muscle of young chicks fed chow diets containing the
creatine analog
1-carboxymethyl-2-iminoimidazolidine (
cyclocreatine) accumulated up to 40 mumol/g wet weight of the synthetic phosphagen
1-carboxymethyl-2-imino-3-phosphonoimidazolidine (cyclocreatine-P2-).
ATP levels were sustained at high values substantially longer in breast muscle of
cyclocreatine-fed chicks, compared to control-fed chicks, during total
ischemia initiated 2 h after injection of both groups with the
beta-adrenergic agonist isoproterenol (5 mg/kg subcutaneous). For example, in chicks fed 0.5%
cyclocreatine for 10-19 days
ATP levels in
isoproterenol-stimulated breast muscles after 1 h of
ischemia at 37 degrees C were 6.1 mumol/g, compared to 1.9 mumol/g for the control-fed group, and after 2 h of
ischemia were 3.5 mumol/g compared to 0.6 mumol/g for controls.
Creatine-P reserves in
isoproterenol-stimulated breast muscles of all dietary groups were essentially exhausted within the first hour of
ischemia. In contrast, breast muscle of chicks fed either 1 or 0.5%
cyclocreatine still contained 28 and 19 mumol/g of
cyclocreatine-P, respectively, after 1 h of
ischemia; after 2 h of
ischemia, the respective
cyclocreatine-P values were 20 and 13 mumol/g.
Isoproterenol-stimulated chick breast muscle provides the first skeletal muscle model system for studying the molecular mechanisms by which dietary
cyclocreatine helps sustain
ATP levels during
ischemia. Although adaptive factors are also involved, it is suggested that a significant portion of the
ATP-sustaining activity of dietary
cyclocreatine in ischemic breast muscle can be attributed to the unique thermodynamic properties of the accumulated
cyclocreatine-P. These properties enable
cyclocreatine-P to continue to thermodynamically
buffer the adenylate system and transport high energy
phosphate throughout the long muscle fibers at cytosolic pH values and phosphorylation potentials well below the range where the
creatine-P system can function effectively. Synergism between glycolysis and this long-acting synthetic phosphagen might well help delay depletion of
ATP levels in skeletal muscles during
ischemia.
Cyclocreatine feeding provides a unique experimental tool for quantitative evaluation of the proposed protective role of
ATP against irreversible cellular damage in skeletal and cardiac muscles during ischemic episodes.