Effects of the creatine analogue beta-guanidinopropionic acid on skeletal muscles of mice deficient in muscle creatine kinase.
To evaluate the effects of phosphocreatine (PCr) and creatine (Cr) depletion on skeletal muscles of mice deficient in muscle creatine kinase (M-CK), we have fed mutant mice a diet containing the creatine analogue beta-guanidinopropionic acid (beta GPA). After 8-10 weeks of feeding, accumulation of the creatine analogue in M-CK-deficient muscles was comparable to that observed in muscles of wild-type mice. Strikingly, and unlike wild types, mutants did not accumulate phosphorylated beta GPA, indicating that MM-CK is the only muscle CK isoform which can phosphorylate beta GPA. In M-CK-deficient muscles there was respective depletion of PCr, Cr and ATP levels to 31, 41 and 83% of normal. The average cross-sectional area of type 2B fibres in gastrocnemius muscles was very much reduced and was similar to type 1 and type 2A fibres which maintained their normal size. The maximal isometric twitch force developed by gastrocnemius-plantaris-soleus (GPS) muscle complexes of beta GPA-treated mutants was reduced by about 30%, but these muscles showed an increased fatigue resistance during 1 and 5 Hz contraction. Mitochondrial enzyme activities in the upper hind limb musculature of null mutants were 20-35% increased by the beta GPA diet. Altogether, these results provide evidence that certain functions of the creatine kinase/phosphocreatine (CK/PCr) system are not eliminated solely by the loss of M-CK.
van Deursen
J
J
Department of Cell Biology and Histology, Faculty of Medical Sciences, University of Nijmegen, The Netherlands.
Jap
P
P
Heerschap
A
A
ter Laak
H
H
Ruitenbeek
W
W
Wieringa
B
B
D000818:Animals; D003401:Creatine / Q000172:deficiency; D003402:Creatine Kinase / Q000172:deficiency*; D004734:Energy Metabolism; D006146:Guanidines / Q000494:pharmacology*; D051379:Mice; D008817:Mice, Mutant Strains; D009119:Muscle Contraction; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D010725:Phosphocreatine / Q000172:deficiency; D011422:Propionates / Q000494:pharmacology*
D006146:Guanidines; D011422:Propionates; D010725:Phosphocreatine; D003402:Creatine Kinase; D003401:Creatine; C005775:guanidinopropionic acid