Creatine and Creatinine Metabolism - Physiological Reviews

1142 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80
On one hand, manipulations of the CK/PCr/Cr system
were shown to induce myopathic changes. 1) Skeletal
muscle of transgenic mice lacking MM-CK and/or sarcomeric
Mi-CK displayed structural and functional alterations
such as impaired burst activity, decreased rate
constants for changes in muscle tension, and abnormal
Ca 2� handling (see sect. VIID). The facts that these mice
survive and reproduce, and that the phenotype is milder
than previously suspected, may indicate that other systems
(e.g., adenylate kinase) take over in part the function
of CK (see sect. VIID). 2) With the caveat that the reagent
may not be sufficiently specific, injection of the CK inhibitor
2,4-dinitrofluorobenzene (DNFB) into the aorta of
rats caused a metabolic myopathy characterized by spontaneous
muscle contractures in the hindlimbs and by
selective destruction of type I fibers in both soleus and
gastrocnemius muscles (233). 3) When fed to experimental
animals, the Cr analog GPA competes with Cr for
uptake into muscle and therefore results in considerable
depletion of the muscle stores of Cr and PCr. In line with
the fact that GPA and its phosphorylated counterpart
PGPA represent poor CK substrates, a variety of pathological
changes have been observed in skeletal muscles of
these animals (see sect. VIIIB) (741, 1125).
On the other hand, many (neuro)muscular diseases
with different underlying defects are accompanied by a
variety of disturbances in Cr metabolism. Examples are
Duchenne muscular dystrophy (DMD) and Becker muscular
dystrophy (BMD), facioscapulohumeral dystrophy,
limb-girdle muscular dystrophy, myotonic dystrophy, spinal
muscle atrophy, amyotrophic lateral sclerosis, myasthenia
gravis, poliomyelitis anterior, myositis, or diabetic
myopathy, to name just a few (for references, see Refs.
639, 826, 955, 1002, 1123). Common findings are increased
Cr concentrations in serum and urine; stimulation of creatinuria
by oral supplementation with Gly or Cr; decreased
urinary Crn excretion; depressed muscle levels of
Cr, PCr, P i, glycogen, and ATP; increased serum CK activities;
as well as an increased MB-/MM-CK ratio in skeletal
muscle, with the latter suggesting induction of B-CK
expression in regenerating muscle fibers. In addition, a
67–86% decrease in Mi-CK activity or mRNA levels was
reported for chickens with hereditary muscular dystrophy
and rats with diabetic myopathy (585, 955). Depending on
the particular muscle disease, these disturbances are
more or less pronounced. Unfortunately, no sufficiently
detailed studies have been published in recent years,
whereas the older investigations were performed mostly
with rather nonspecific analytical methods. Therefore, the
above-mentioned findings await corroboration and expansion,
which will hopefully allow us to unravel potential
causal links between individual muscle diseases and disturbances
of Cr metabolism.
In DMD, increased plasma membrane fragility and
subsequent leakage of cytosolic components due to dys-
trophin deficiency are generally accepted to be the primary
defects. The muscle concentrations of Cr, PCr, and
ATP, the ATP/ADP, PCr/Cr, and PCr/ATP ratios, as well as
the phosphorylation potential are significantly decreased,
whereas the calculated ADP concentration and intracellular
pH are increased (88, 143, 211, 472). Conversely,
serum [Cr] is increased, resulting in creatinuria, in considerably
reduced tolerance toward orally administered
Cr, and, very likely due to competition of Cr and GAA for
reabsorption in the kidney, in elevated urinary excretion
of GAA. The total bodily Cr pool is reduced because of
both muscle wasting and a reduced Cr concentration in
the remaining muscle mass, with the consequence that
Crn production and urinary Crn excretion are largely
decreased. By use of radioactively labeled Cr, Cr turnover
was shown to be increased in DMD patients relative to
controls, with half times for the decrease in isotope content
of 18.9 � 5.1 and 39.8 � 2.6 days, respectively (245).
This latter finding may be due either to impaired Cr
uptake into muscle (57) or to an impaired ability of muscle
to retain Cr.
Most probably due to leakage of the plasma membrane
and to continued necrosis of immature muscle
fibers, both the total CK activity and the proportion of
MB-CK in serum are dramatically increased (79, 190, 222,
755). Finally, disturbances of ion gradients across the
plasma membrane were observed in skeletal muscle from
DMD patients. The muscle concentration of Na � as well
as the free intracellular [Ca 2� ] are increased, whereas the
muscle levels of K � and P i are decreased. In serum, on the
other hand, [K � ], [Ca 2� ], and [P i] are increased, whereas
[Na � ] and [Cl � ] are decreased (see Refs. 143, 199, 755).
Disturbances very similar to those seen in DMD were
observed in mdx mice that display the same primary
defect as DMD patients, namely, dystrophin deficiency,
and in other dystrophic animal strains (see Refs. 143, 199,
201–203, 790, 799). Additionally, in skeletal muscles of
mdx mice, the resting membrane potential was shown to
be “decreased” from �70 to �59 mV (see Ref. 199).
Remarkably, all pathological changes, i.e., muscle fiber
necrosis as well as the disturbances in membrane permeability,
in Cr and high-energy phosphate metabolism, and
in serum CK activities, were not evident in mdx mice at
birth, but only developed after 2–6 wk of life (202, 799,
982). Consequently, dystrophin deficiency alone does not
seem to be sufficient to induce muscle damage, thus
calling for other factors that may act in conjunction with
dystrophin deficiency to bring about plasma membrane
damage and muscle cell necrosis.
Two hypotheses may be put forward to explain how
disturbances in Cr metabolism may contribute to the
progression of DMD and of other muscle diseases (see
also Ref. 1123). 1) Loike et al. (571) have shown that
increasing concentrations of extracellular Cr downregulate
Cr transport activity in rat and human myoblasts and