1 Department of Physiology, State University of New York, Health Science Center at Syracuse, Syracuse, New York 13210; and 2 Department of Cell Biology and Histology, University of Nijmegen, 6500 HB Nijmegen, The Netherlands
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ABSTRACT |
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Alterations in the competency of the creatine kinase system
elicit numerous structural and metabolic compensations, including changes in purine nucleotide metabolism. We evaluated molecular and
kinetic changes in AMP deaminase from skeletal muscles of mice
deficient in either cytosolic creatine kinase alone
(M-CK/
) or also
deficient in mitochondrial creatine kinase
(CK
/
) compared
with wild type. We found that predominantly fast-twitch muscle, but not
slow-twitch muscle, from both
M-CK
/
and
CK
/
mice had much
lower AMP deaminase; the quantity of AMP deaminase detected by Western
blot was correspondingly lower, whereas AMP deaminase-1
(AMPD1) gene expression
was unchanged. Kinetic analysis of AMP deaminase from mixed muscle
revealed negative cooperativity that was significantly greater in
creatine kinase deficiencies. Treatment of AMP deaminase with acid
phosphatase abolished negative cooperative behavior, indicating that a
phosphorylation-dephosphorylation cycle may be important in the
regulation of AMP deaminase.
muscle energetics; adenine nucleotides; inosine monophosphate; enzyme kinetics; enzyme phosphorylation
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INTRODUCTION |
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THE ONSET OF CONTRACTION by skeletal muscle can rapidly
increase the rate of ATP hydrolysis ~100-fold within seconds.
Skeletal muscle sustains these transitions via a high-energy phosphate network that facilitates the maintenance of the free energy of ATP
hydrolysis (GATP). This
network attenuates changes in muscle adenylates via disequilibrium of
key energy buffering reactions catalyzed by creatine and adenylate
kinase (8, 28).
Creatine kinase (CK) effectively buffers both temporal and spatial changes in ATP concentration occurring during exercise by mediating the near-equilibrium phosphotransferase reaction of phosphocreatine (PCr) and ADP, yielding creatine (Cr) and ATP
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AMP deaminase is a tetrameric enzyme composed of identical 80-kDa subunits controlled, at least in part, by AMP concentration, allosteric modulators such as ADP and inorganic phosphate (20), and ATP turnover associated with muscle contraction (13). During intense contractions, AMP deamination can occur at an extremely high rate in fast-twitch muscle, sufficient to deplete the ATP concentration by ~50% (20). Once formed, IMP is retained within the myocyte until muscle energy balance is restored sufficiently for reamination back to AMP via the purine nucleotide cycle (18).
Feeding the creatine analog -guanidinopropionic acid (
-GPA) to
deplete the muscle creatine-phosphocreatine pool produces a functional
CK system deficiency that results in several compensatory metabolic and
morphological changes (9, 14, 23). In particular, the activity of
muscle AMP deaminase is decreased as much as ~85% in fast-twitch
muscle (10, 19). Interestingly, this occurs with no loss of ability to
form IMP during exercise. It is presently unclear whether these changes
are a result of the loss in the CK energy system per se or secondary to
specific changes in phosphocreatine concentration and/or
-GPA itself.
The purpose of this study was to determine the nature and
extent of changes induced in AMP deaminase in the muscles of transgenic mice deficient in CK (16, 25, 29). Thus we have performed studies on
AMP deaminase from skeletal muscles of mice possessing both cytosolic
and mitochondrial isoforms of CK (wild type), mice deficient only in
the cytosolic CK isoform
(M-CK/
),
and mice with neither cytosolic nor mitochondrial CK isoforms (CK
/
).
Specifically, AMP deaminase gene expression, activity, and kinetics
have been investigated. Further in vitro experiments have established
the likelihood that phosphorylation may play a key role in regulating
AMP deaminase kinetic properties.
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METHODS |
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CK-deficient strains.
Transgenic mice with a homozygous null mutation for the gene encoding
the M-subunit of CK
(M-CK/
) have no
cytosolic CK (23, 24) but do express the mitochondrial isoform.
Transgenic mice deficient in both the cytosolic and mitochondrial isoforms (CK
/
)
were generated by crossing
M-CK
/
and
ScCKmit
/
mice (16).
Each group was composed of five female mice.
Muscle sampling.
Mice were anesthetized with 3-bromoethanol; the soleus, superficial
vastus lateralis, and the mixed-fiber muscle of the upper and lower
hindlimb were removed and frozen in liquid nitrogen and stored at
80°C until use. The mouse soleus is composed primarily of
slow-twitch red fibers (4); the superficial vastus lateralis is
expected to be primarily fast-twitch white fibers as is the superficial
portion of the mouse gastrocnemius muscle (4) because there is
generally excellent correspondence in fiber-type composition between
the superficial quadriceps and gastrocnemius muscle in other rodents
(1) and these knockout mice do not appear to exhibit significant
changes in muscle fiber composition (cf. Refs. 16, 22, 23).
Enzyme assays.
Frozen skeletal muscles/sections were extracted and assayed for AMP
deaminase activity by direct assay of IMP formation via HPLC analyses,
as described in detail previously (21). Reaction conditions were linear
over the time of measurement and proportional to the amount of muscle
extract used. Total AMP deaminase activity was determined on whole
muscle homogenates, and kinetic analyses were performed on 13,000 g supernatants using an extensive
range of AMP concentrations from 0.04 to 15 mM, as described previously (11). To minimize the potential for enzyme modification/inactivation, we did not further process the supernatants (dialyze to eliminate effectors); however, muscle extracts were diluted ~2,000-fold for the
assay procedure. This would likely eliminate possible confounding
influences of soluble effectors present in the muscle. There were no
changes in the 80-kDa signal and no accumulation of any
lower-molecular-weight immunoreactive AMP deaminase species in the
wild-type or CK/
samples over the time for kinetic determination. Maximal velocities and
Michaelis-Menten
(Km) constants
were calculated by double-reciprocal plots.
Treatment of muscle extracts with acid phosphatase.
The potential role of phosphorylation in governing AMP deaminase muscle
kinetics was tested by treating muscle extracts from creatine-deficient
mice with acid phosphatase. Acid phosphatase prepared from wheat germ
(Sigma) was added to aliquots of the soluble cell fractions of
M-CK/
and
CK
/
mixed muscle at
a dose of 10 U/ml. These mixtures were incubated at room temperature
for 30 min, after which they were used for kinetic analysis of AMP
deaminase as described above. Preliminary experiments demonstrated that
these conditions of dose and time were sufficient to elicit the maximal
acid phosphatase-induced response in AMP deaminase kinetics. There were
no accumulations of lower-molecular-weight immunoreactive AMP deaminase
species with acid phosphatase treatment; however, the 80-kDa AMP
deaminase signal was slightly reduced in both wild-type and
CK
/
mice (~15%).
RNA analyses. Frozen mixed-muscle samples were weighed and pulverized in a mortar chilled with liquid nitrogen. Total cellular RNA was isolated using a kit (Ultraspec RNA; Biotecx, Houston, TX). Total RNA was quantitated by absorbance at 260 nm, and mRNA was determined by slot blot analysis of 0.25 and 0.5 µg of total RNA using end-labeled oligo(dT)12-18 (6).
Plasmid Bluescript containing the rat AMP deaminase-1 (AMPD1) cDNA insert was linearized using the restriction enzyme Stu I (New England Biolabs). A riboprobe was generated using T3 RNA polymerase, following the kit instructions (Riboprobe Combination System-T3/T7; Promega). To confirm mouse AMPD1 transcript size, we performed Northern blots with this riboprobe after agarose gel electrophoresis of 5 and 10 µg of total RNA. Protocols described in detail previously (12) were followed except that RNA was transferred to nylon membranes (MSI MagnaCharge; Fisher). AMPD1 transcript abundance was determined by probing slot blots loaded with 5 and 10 µg of total RNA. Radioactive bands identified on exposed X-ray film were digitized to an eight-bit gray scale image at 600 dots per inch (dpi) using a flatbed scanner (Hewlett Packard), with the darkest area of the region of interest set to 255 and the lightest to 0. Analyses were performed on a Macintosh computer using the gel-plotting macro of the public domain National Institutes of Health (NIH) Image software (version 1.60).Western blot. Western blot analysis was performed using muscle samples extracted exactly as described previously (19) using the same polyclonal antiserum raised against purified rat skeletal muscle AMP deaminase (7). Developed nitrocellulose membranes were digitized and analyzed using NIH Image as described above.
Statistics.
One- or two-way analyses of variance were used to evaluate significant
differences among means. Tukey's -procedure was used to calculate
least significant difference at P < 0.05.
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RESULTS |
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AMP deaminase activity.
Total muscle AMP deaminase activity is altered by CK deficiencies in a
fiber-type-specific fashion. As shown in Table
1, AMP deaminase activity was markedly
reduced (by 70-75%) in the fast-twitch superficial vastus
lateralis muscle from both single and double CK-deficient mice, whereas
no change was detected in the soleus muscle containing predominantly
slow-twitch red fibers. Citrate synthase activity, a marker of
oxidative capacity, was increased in fast-twitch (200%) and
slow-twitch (80%)
CK/
muscle (Table
1).
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AMP deaminase Western blot data.
Figure
1A
shows a representative Western blot for AMP deaminase from muscle of
M-CK/
and wild-type
mice. The apparent molecular mass of AMP deaminase in mice of 80 kDa
(cf. Fig. 1A) was similar to that
found in rat skeletal muscle (19). The AMP deaminase protein in
M-CK
/
mice was less
abundant than in wild-type mice; increased amounts of smaller
immunoreactive species having apparent molecular masses of ~60 and
~56 kDa were often observed in CK-deficient muscle (cf. Fig.
1B). Densitometric analysis of
Western blots of mixed-fiber muscle, illustrated in Table
3, showed that
the 80-kDa AMP deaminase protein was significantly decreased in
M-CK
/
(by 50%) and
CK
/
(by 80%)
animals. Blot signals were proportional to protein load applied to the
gel. The decreases were similar or greater in the vastus lateralis
muscle section (cf. Table 3). In contrast and in agreement with the
activity data (Table 1), the AMP deaminase protein of the soleus muscle
was not significantly different in CK
/
mice.
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AMP deaminase gene expression.
Data regarding AMPD1 gene expression
are somewhat more complex (Table 4).
Results of Northern blots showed expression to be marginally lower with
CK deficiency, when expressed relative to the constant amount of total
RNA applied to the blot. However, if
AMPD1 gene expression is corrected for
the relative amount of mRNA, as assessed by
oligo(dT)12-18 hybridization,
the decline in AMPD1 signal was
significant in the
CK/
mice. Yet, the
yield of total RNA was progressively higher from the
M-CK
/
and
CK
/
than from
wild-type muscle. If AMPD1 gene
expression is corrected for this increased amount of total RNA per
gram, there was no change in AMPD1
mRNA abundance per gram of muscle. Thus it appears that an unchanged
amount of AMPD1 mRNA was diluted by an
increase in total muscle RNA found in the CK-deficient muscle.
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AMP deaminase kinetics.
Complex kinetic changes in AMP deaminase were observed in the
mixed-fiber lower hindlimb muscle of CK-deficient mice. Figure 2 is a double-reciprocal plot of data from
wild-type and
M-CK/
mice
(results for CK
/
mice were similar to
M-CK
/
; data not
shown). The pronounced concave nature of the double-reciprocal plots
for all groups reflects negative cooperativity. The kinetic changes
were analyzed by independently evaluating the biphasic quasilinear
portions of the double-reciprocal plot, representing two ranges of AMP
concentration from 0.04 to 0.15 mM and from 0.2 to 15 mM, as
illustrated in Fig. 2. The
Km thus derived
are presented in Table 5. The
Km of AMP
deaminase over the low AMP concentration range is significantly lower
in muscle of single and double CK-deficient mice than in muscle of
wild-type mice. It is noteworthy that, unlike normal rat mixed-fiber
muscle (19), muscle from all three groups of mice had AMP deaminase
that exhibited a higher substrate affinity over the lower range of AMP
concentrations.
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Effect of phosphatase treatment.
Incubation of muscle extracts with purified acid phosphatase induced a
remarkable change in enzyme kinetics. Figure
3 shows double-reciprocal plots of AMP
deaminase from CK/
mice after incubation in buffer with or without acid phosphatase. Incubation without acid phosphatase showed the expected biphasic kinetic pattern (cf. Figs. 2 and 3). Acid phosphatase treatment abolished the negative cooperativity, yielding a single, essentially linear, double-reciprocal plot. Similarly, essentially linear kinetic
double-reciprocal plots were induced by acid phosphatase treatment in
M-CK
/
and wild-type
(data not shown) mice. Interestingly, the five- to eightfold increases
in the phosphoserine-, phosphothreonine-, and phosphotyrosine-specific
antibody signal in the 80-kDa AMP deaminase gel position for the
CK
/
mouse muscle
(compared with the wild-type mouse using equivalent AMP deaminase loads
on the gel) were eliminated (88-93%) by acid phosphatase
treatment (unpublished observations). Although confirmation is
necessary, it appears that the AMP deaminase kinetic change coincides
with specific amino acid phosphorylation-dephosphorylation.
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DISCUSSION |
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CK deficiencies in skeletal muscle profoundly alter the morphological and metabolic properties of muscle tissue in ways that likely serve to compensate for the loss of ATP buffering capacity. Transformations occurring in the phenotype of CK-deficient muscle include alterations in contractile function (3, 22, 26), energy-transducing metabolic pathways (16, 22), and Ca2+ management (16, 22). The present work describes adaptive changes in AMP deaminase evident in CK-deficient muscle that we believe reveal specific regulatory mechanisms of fundamental importance for the control of adenine nucleotide metabolism in muscle.
Fast-twitch CK-deficient muscle exhibits markedly lower AMP deaminase
activity that can be attributed to a loss of native tetrameric enzyme
on the basis of the decreased quantity of the full-size (80 kDa)
monomeric subunit as quantified by Western blot following SDS-PAGE.
These results parallel the pattern established in rat skeletal muscle
during creatine depletion using the creatine analog -GPA (19). In
contrast, AMP deaminase activity in the predominantly slow-twitch red
soleus muscle was similar for
M-CK
/
,
CK
/
, and wild-type
mice; this finding was corroborated by the similar abundance in Western
blot signal between wildtype and
CK
/
mice (Table 3).
These results expand the report (26) of the unique fiber-specific
responses to CK deficiency in showing the distinctions between
fast-twitch and slow-twitch skeletal muscle for AMP deaminase.
The extensive expansion of mitochondrial content in deficient mice,
indicated by increases in citrate synthase activity, was nonuniform in
different muscles and not strictly related to changes in AMP deaminase
(Tables 1 and 2). Citrate synthase activity was elevated in
CK-deficient hindlimb mixed-fiber muscle, as found by others (16, 22).
The greatest differences in citrate synthase activity were found in the
superficial vastus muscle, where
CK/
> M-CK
/
> wild type;
AMP deaminase, however, was decreased similarly in the single and
double CK-deficient animals. Changes evident in citrate synthase and
AMP deaminase seem to be related to fiber composition. In predominantly
fast-twitch superficial vastus muscle, differences in the two enzymes
are reciprocal, whereas, in the predominantly slow-twitch soleus
muscle, higher citrate synthase activity exists without diminished AMP
deaminase. Thus we interpret the more modest changes in AMP deaminase
of the mixed-fiber muscle of the hindlimb as an averaged response based
on fiber composition. There have been no remarkable changes in fiber
type, size, or distribution reported for muscle of
M-CK
/
mice (27),
although there is precedence for such changes induced by creatine
analog feeding in normal mice (9) and in
M-CK
/
mice (23).
Whether gross alterations in muscle-fiber type or more subtle
differences in myosin expression exist in the superficial vastus or
soleus muscles used in this study is not presently known.
Our results argue that the decreased activity of AMP deaminase is not
attributed to altered gene expression, based on the similar AMP
deaminase mRNA abundance across groups (cf. Table 4). It is possible
that translation efficiency of the AMP deaminase mRNA is diminished
and/or that degradation, and consequently turnover, of AMP
deaminase protein is increased. The frequent observation of smaller
size immunoreactive species (~56 and 60 kDa) in Western blots (Fig.
1) suggests elevated proteolysis of the enzyme; if true, an increased
turnover of the protein would be expected. These smaller, presumably
inactive, species are even observed at low levels in blots of normal
muscle (Fig. 1). In rats fed a diet containing -GPA, the lower
apparent molecular weight species accumulated to a significant degree
during the course of AMP deaminase enzyme loss (11, 19).
Kinetic experiments revealed that AMP deaminase from mixed muscle of
wild-type and deficient mice displayed negative cooperativity (Fig. 2);
furthermore, AMP deaminase from
M-CK/
and
CK
/
exhibited
significantly lower
Km values
(increased affinity) than the enzyme from wild-type muscle when
evaluated at low-AMP concentrations (<0.2 mM) (Table 5). In both
M-CK
/
and
CK
/
mice, the
absence of CK is associated with a loss of total AMP deaminase activity
that is coupled to increased substrate affinity at low-substrate
concentrations. A similar situation is established with creatine
depletion in rats fed
-GPA (11). Calculated flux through AMP
deaminase at low physiologically relevant AMP concentrations, using the
measured kinetic constants (Table 5) and maximal activities (Table 2),
shows that the higher substrate affinity partially compensates for the
lower quantity of enzyme. Thus it may be expected that AMP deaminase
would function to effectively produce IMP during intense contraction
conditions in vivo despite its lower enzyme protein abundance, similar
to that observed for
-GPA-treated muscle (10, 19).
Several years ago, Tovmasian et al. (17) showed that rat skeletal
muscle AMP deaminase could be phosphorylated by the rat brain protein
kinase C. Thus it was important to evaluate whether phosphorylation of
AMP deaminase could be the basis for the kinetic alteration seen in
enzyme from M-CK/
and CK
/
mice. The
remarkable effect that treatment with acid phosphatase had in
abolishing the negative cooperativity kinetic effect, similar to that
observed in muscle from
-GPA-fed rats (11), is consistent with a
critical role for a phosphorylation-dephosphorylation cycle in the
control of AMP deaminase activity in vivo. If further experiments support this hypothesis, AMP deaminase
phosphorylation-dephosphorylation may prove to be of critical
importance in the management of the muscle adenine nucleotide pool
during exercise.
The specific mechanism(s) linking functional changes in the CK system
to altered AMP deaminase activity is not known. CK and AMP deaminase
buffer decrease in the GATP by
facilitating the consumption of ADP during intense muscle contraction
conditions. The synergistic roles of these enzymes suggest that a
chronically altered energy balance resulting from CK system
deficiencies might exert a regulatory effect on AMP deaminase. This may
also be evident to a modest extent in resting muscle. Our working
hypothesis is that a modified energy state (cf. Ref. 5) and/or
Ca2+ management (cf. Ref. 16),
established in resting muscle by loss of the CK energy buffer system,
favors phosphorylation of AMP deaminase; this, in turn, induces
negative cooperativity kinetic behavior (Fig. 3). The resulting
elevated activity at physiological AMP concentrations
(Km low at
~0.02 mM), in concert with previously identified noncovalent
modulators of AMP deaminase, such as ADP, activates deamination. This
serves to attenuate declines in
GATP during periods of high
energy demand. Similarly, the loss in ATP buffering capacity
and/or its effects on H+
and phosphate homeostasis could be involved. It is intriguing to
speculate further that the altered conformation due to phosphorylation increases the susceptibility of AMP deaminase to proteolytic
degradation. This could potentially account for the increased abundance
of the 56- and 60-kDa AMP deaminase fragments identified in the Western blots.
In summary, metabolic changes brought about by CK deficiencies include changes in the quantity of AMP deaminase activity and the 80-kDa subunit enzyme. Kinetic behavior exhibiting negative cooperativity is greater in the enzyme from deficient mice. If muscle metabolism of the transgenically altered mice is similar to that observed in creatine-depleted rats (11, 19), we would predict that, despite the smaller amounts of enzyme, the ability to deaminate AMP during intense exercise may be maintained by increases in the enzyme's affinity for AMP.
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ACKNOWLEDGEMENTS |
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The expert technical assistance of Judy Freshour and Mary Graziano (SUNY Health Science Center) and Mr. Frank Oerlemans (University of Nijmegen) is gratefully recognized. The polyclonal antibody and cDNA probe to AMPD1 were the kind gift of Dr. Richard L. Sabina (Medical College of Wisconsin, Milwaukee, WI).
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FOOTNOTES |
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This study was supported by National Institutes of Arthritis and Musculoskeletal and Skin Diseases Grant AR-21617 and by a program grant from the Dutch organization for Scientific Research (Medical Sciences). J. W. E. Rush was the recipient of a Natural Sciences and Engineering Research Council of Canada Postgraduate Scholarship B predoctoral fellowship.
Address for reprint requests: R. L. Terjung, Biomedical Sciences, College of Veterinary Medicine, E 102 Vet. Med. Bldg., Univ. of Missouri, Columbia, MO 65211.
Received 10 November 1997; accepted in final form 5 February 1998.
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