Skeletal muscle possesses the unique capacity to consume energy at rates that are hundreds of times greater than resting values. This large range of energy demands presents the muscle cell with the challenge of maintaining an adequate energy state. One of the principle enzymes involved in preventing a precipitous decline in the cellular energy state at high energy demands is AMP deaminase (AMPD). The purpose of this review is to highlight the role that the enzyme AMPD plays in maintaining a viable energy state in skeletal muscle, particularly during conditions where energy demands temporarily outpace the capacity for energy supply.

Energy state

The principle function of skeletal muscle is to generate force and facilitate movement. The energy costs associated with maintaining muscle function and viability are supported by the hydrolysis of high energy phosphate bonds of ATP. The primary energy consumer in skeletal muscle during contractions is the myosin ATPase which accounts for approximately 70% of the total ATP consumed by skeletal muscle, while the remaining 25-30% of ATP hydrolysis supports the maintenance of the large calcium gradient between the cytoplasm and the sarcoplasmic reticulum (~1:10,000) via the sarcoplasmic reticulum ATPase (SERCA) (see review (1)). Thus, the vast majority of the energy from ATP hydrolysis during muscle contractions is devoted to the cellular work involved in both the actomyosin-ATPase and the maintenance of the calcium gradients necessary for the activation and deactivation of the myofilaments.

The capacity for the high energy phosphate bonds of ATP to provide energy for the cellular work of maintaining ion gradients and the cross-bridge cycle is defined by the Gibbs free energy of ATP hydrolysis. The Gibbs free energy of a chemical reaction is a measure of the degree to which a reaction is from reaching equilibrium (2). Simply put, the amount of free energy liberated from the ATP hydrolysis reaction (ATP ADP + Pi ) is a function of the relative concentrations of ADP and inorganic phosphate (Pi) to ATP, as defined below (equation 1).

           GATP=GoATP+RTln([ADP]*[Pi]/[ATP]) (equation 1)

The GoATP is the free energy of ATP at defined standard conditions (-32 kJ/mol (3)), R is the ideal gas constant, and T is the temperature in Kelvin. As the concentration of ADP and Pi increase, and/or the concentration of ATP decreases, the energy available from ATP hydrolysis declines. The actual amount of energy available is particularly important since it may be limiting for some ATPase reactions in the cell and, therefore, may effect muscle contractions.

The free energy available from ATP must be put in the context of both the content and rate of ATP hydrolysis in skeletal muscle. The rate of ATP hydrolysis in skeletal muscle can be as great as 10 µmol/g/s (3, 4) which would result in the complete depletion of the existing content of ATP (~4-7 µmol/g) in less than one second, in the absence of any ADP rephosphorylation. Fortunately, the supply of ATP occurs rapidly and under most conditions is sufficient to maintain adequate content of ATP for cellular viability. In fact, the rate of ATP hydrolysis is matched by the rate of ATP supply without measurable changes in ATP over a wide range of ATP demands (up to very intense short-term near-maximal exercise) (5). The sources of ATP during sustained contractions are primarily oxidative phosphorylation and to a smaller degree glycolysis. Additionally, phosphocreatine (PCr) via the creatine kinase reaction (reaction 1) also serves as a limited source of high-energy phosphate, and as an intracellular buffer of ADP, limiting the decline in ATP during transitions from low to high ATP demands.

PCr + ADP + ßH+ g Cr + ATP (reaction 1)

The importance of PCr and the creatine kinase reaction has been rigorously investigated with the use of models of PCr depletion as well as transgenic models of CK deficiency (6 - 12).

When ATP consumption is sufficiently out of balance with ATP supply, a decline in ATP is observed, and this is precisely where the activity of the coupled reactions of adenylate kinase (AK) and AMP deaminase (AMPD) are most important. The primary effect of AK and AMPD on adenine nucleotide content is to limit the accumulation of ADP when ATP turnover rates are high. This is particularly clear during conditions when the rate of ATP is high enough to cause a net reduction in ATP content. Consider for example, the fact that a 40% decline in ATP would result in a 160 fold increase in ADP if all of the decline in ATP was converted only to ADP (13). However, the range of metabolically available ADP concentrations that have been reported in skeletal muscle is on the order of only 10 fold (~15 to 150 nmol/g muscle weight (13, 14)). It is important to note that similar constraints on the concentration of Pi are not observed, as the concentration of Pi largely mirrors reductions observed in PCr and can reach concentrations near 20 µmol/g muscle weight during high energy demands (15). Thus, limiting ADP accumulation is critical to maintain an adequate ratio of ADP and Pi to ATP and preserve sufficient energy available from ATP hydrolysis (equation 1). The manner in which ADP accumulation is limited by AK and AMPD is also closely tied to the regulation of the concentration of AMP. The concentration of free AMP in skeletal muscle is estimated to range from approximately 0.09 to 25 nmol/g muscle weight (16). This is quantitatively insignificant (< 0.5%) relative to the changes observed in ATP which can be ~3-4 µmol/g muscle weight. Thus, AK and AMPD activity have a pivotal role in maintaining the free energy of ATP hydrolysis.

During conditions when the rate of ATP hydrolysis outpaces the rate of ATP synthesis and a decline in ATP is observed, the AK reaction is critical in limiting an inordinate increase in the concentration of ADP. Adenylate kinase enzyme capacity in skeletal muscle is extremely high, and is considered to be near equilibrium under most conditions (17). The AK reaction consists of the phosphorylation of an ADP molecule by another ADP resulting in the formation of an ATP and an AMP (reaction 2). As alluded to above, the accumulation of AMP is also limited by the AMP deaminase reaction (reaction 3) which catalyzes the removal of an amino group from AMP forming IMP and ammonia. In contrast to AK, the reaction catalyzed by AMPD is irreversible at physiological condi-tions. Therefore, the recovery of adenine nucleotides lost during high energy demands must be recovered by the reamination of IMP. This occurs through the reactions of adenylosuccinate synthetase and adenylosuccinate lyase, which along with AMPD make up the reactions of the purine nucleotide cycle (see reviews (18 - 20).

                      2ADP   ATP + AMP  (reaction 2)
            AMP + H2O IMP + NH3    (reaction 3)
          2ADP + H2O ATP + IMP + NH3   (reaction 4)

The high capacity of AMPD in skeletal muscle during the high energy demands of intense muscle contractions keeps the AK reaction proceeding in the direction of AMP formation and on balance, IMP formation. This has been illustrated in rat skeletal muscle where the decline in ATP due to the high energy demands of muscle contractions, is matched by an increase in IMP accumulation (Fig. 1) (21 - 23). Furthermore, this also occurs in human muscle during intense exercise bouts (24 - 26). Thus, when ATP hydrolysis outpaces supply, large accumulations of ADP and AMP are preempted by the coupled reactions of AK and AMPD, facilitating the accumulation of IMP and NH3.

Fig. 1. The decline in muscle ATP content during intense contractions in fast-twitch muscle is matched by a stoichiometric increase in IMP content. Adapted from Meyer, et al., (22) with permission.

Regulation of AMPD

While the enzymatic capacity of AMPD in skeletal muscle is extremely high, many studies have demonstrated that AMPD is highly regulated. First, AMPD in skeletal muscle is activated by a reduction in intracellular pH (27), and in vitro kinetics have demonstrated optimal activity at a pH of 6.5 (28). Second, AMPD is allosterically regulated by ADP, AMP and Pi. Increases in ADP and AMP concentrations have an activating effect, while increases in Pi are inhibitory (29, 30). Third, AMPD binds to myosin which causes an increase in AMPD activity (31 - 34). Furthermore, an increase in AMPD binding to myosin occurs with muscle contractions and may suggest that the localization of AMPD to sites of high ATP turnover is important for effective enzyme activity (35, 36). Fourth, AMPD enzyme kinetics are enhanced by phosphorylation (37), however the kinase(s) responsible for this activation has yet to be fully characterized. Interestingly, the activation of AMPD in skeletal muscle also requires the sustained ATP turnover of active contractions even if the intracellular conditions would be expected to favor activation of AMPD (low pH, high ADP and AMP) (38). Thus, the regulation of AMPD favors enzyme activation during conditions of high energy demands and sustained ATP turnover.

The activation of AMPD and subsequent IMP accumulation is almost strictly a characteristic of fast-twitch skeletal muscle. Work on rodent muscle has shown that in the absence of severe ischemia and high rates of tetanic contractions, significant accumulation of IMP via AMPD does not occur in slow-twitch high oxidative muscle (22, 23, 27, 39). This distinction between fast and slow-twitch muscle is not solely due to differences in oxidative capacity. At high energy demands ATP degradation and IMP accumulation is clearly apparent in high oxidative fast-twitch muscle, which has higher oxidative capacity than slow twitch muscle (23). Further, when energy demands are more moderate, fast-twitch red muscle is more resistant to a loss of adenine nucleotides, consistent with the higher capacity for ATP synthesis (21).

AMPD deficiency

Almost 30 years ago, a defect in AMPD activity was characterized in patients with exercise related symptoms (40). Since then, AMPD deficiency has been characterized as "the most common muscle enzyme defect in man" (41), since a defect in AMPD activity is found in approximately 2% of muscle biopsies (42 - 44). The symptoms associated with AMPD deficiency range from being asymptomatic to severe exertional myalgia and other exercise related pain (43 - 46). In general, controlled studies examining the consequences of AMPD deficiency have not reported a clear picture relating AMPD deficiency and impaired muscle function. For example, in a study by Norman et al., healthy and AMPD deficient subjects were asked to perform a high-intensity cycling test, which consists of a short explosive cycling bout (47). Muscle power was measured during the test and biopsies were taken immediately following the test in order to measure relevant metabolites. In this study, no differences in mechanical power output were observed in AMPD deficient and normal subjects, even though the IMP accumulation was only significant in the normal controls (47). Another study by De Ruiter et al. (48) examined muscle function during repeated bouts of exercise in subjects with or without AMPD deficiency and found mixed results. Five of the 8 subjects with AMPD deficiency presented prolonged muscle relaxation, and were unable to complete the exercise protocol while the remaining 3 AMPD deficient subjects exhibited no functional difference from control subjects (48). These two studies illustrate that although functional complications have been associated with AMPD deficiency, an absolute functional impairment is not evident.

Potential consequences of a decline in the energy state

Functional consequences associated with AMPD deficiency have been attributed to the effect that elevated cellular ADP concentrations have on the cellular energy state. As alluded to above, intracellular ion gradients can be sensitive to changes in a reduction in energy available from ATP. For the purposes of this review, we will discuss the energy requirements of maintaining the calcium gradient in skeletal muscle as this has been found to be sensitive to a decline in energy from ATP, over physiological conditions.

The gradient between cytosolic calcium and the calcium sequestered in the sarcoplasmic reticulum is ~1:10,000 at rest and as a result, the maintenance of this gradient accounts for a large portion of skeletal muscle ATP turnover during contractions (1, 49). The energy required to maintain the resting concentration of cytosolic calcium is worth exploring for two reasons: first, if cytosolic calcium concentration is not rapidly restored following a contraction, force generation will continue resulting in muscle contracture; second, the maintenance of the resting cytosolic concentration of calcium by the sarcoplasmic reticulum ATPase is thought to be particularly sensitive to a fall in the energy available from ATP hydrolysis. Work by Dawson, Gadian and Wilkie more than 25 years ago (50) examined the relationship between the slowing of muscle relaxation and the calculated free energy of ATP hydrolysis in frog gastrocnemius. In that study, they found a clear correlation between the calculated decline in energy from ATP hydrolysis and the decline in the rate constant of muscle relaxation (Fig. 2) (50). Further, from this correlation, the minimum energy from ATP required to obtain relaxation could be extrapolated. The value determined as the minimum energy required to obtain relaxation fit with other estimates of the cost of maintaining the resting intracellular calcium gradient between the cytosol and the SR (-48 kJ/mol at 37°C (51)). Recent work has also shown that ADP has a more direct effect on SERCA function in skeletal muscle. A study by Macdonald and Stevenson has shown that ADP at concentrations near 1 mM causes leakage of calcium from the SR through SERCA in fast-twitch muscle fibers, effectively reducing the capacity for SERCA to maintain an adequate intracellular gradient (52). In addition, other work by Tian and colleagues found that the cardiac contractile reserve was sensitive to changes in the free energy available from ATP (53 - 55). Further, the impairment in contractile reserve was the result of an inability to control intracellular calcium. Thus, they hypothesized this impairment is caused by reduced SERCA activity due to reduced energy available from ATP hydrolysis (53 - 55). Thus, the regulation of intracellular calcium concentration has been found to be intimately correlated with impaired contractile function and a decline in the energy available from ATP. These studies demonstrate the importance of limiting inordinate increases in metabolites that would result in less energy from the hydrolysis of ATP, most notably Pi and/or ADP.

Fig. 2. Muscle relaxation rate constant as a function of the energy available from ATP (GATP). Adapted from Dawson et al., (50) with permission. The original data obtained at 4°C (see insert) have been recalculated to values expected at 37°C (main panel).

The consequences of not limiting large ADP accumulation during contractions are not all necessarily a result of a decline in the cellular energy state. ADP accumulation may impact on a fundamental process of skeletal muscle, the actin and myosin cross-bridge cycle. Studies examining the effect of elevated ADP concentrations on cross-bridge cycling have found that, if sufficiently high, ADP can slow cross-bridge cycling (56, 57). The functional result of slowed cross-bridge kinetics include, increased peak tension due to a higher number of bound cross-bridges, slower rate of force development, and slowed relaxation (52, 56, 58, 59). However, the range of ADP concentrations normally found in vivo is sufficiently small that an ADP dependent effect on cross-bridge kinetics is not expected (14).

Transgenic AK deficiency as a model to examine AMPD

Recently, new evidence illustrating the relationship between muscle capacity for AMP deamination and the protection of the cellular energy state has been reported. Two studies by Hancock et al., examined both the consequence of adenylate kinase deficiency on ADP accumulation and muscle function during high energy demands (60, 61). The model employed in these studies was the transgenic knockout of the Adenylate kinase 1 isoform (62), which is highly expressed in skeletal muscle. As a result of skeletal muscle AK deficiency, AMPD capacity would be severely restricted, since AMP would not be produced by the transphosphorylation of 2 ADPs. While AMPD1-/- mice would be the most direct means of establishing AMPD activity deficiency in muscle, development of these animals has apparently been problematic. Therefore, the use of AK deficiency in muscle is a valuable model to determine what energetic and functional consequences would result in the context of AMPD deficiency. The AMP deamination capacity of AK1 deficient muscle was challenged by eliciting tetanic contractions at increasingly demanding contraction conditions (30, 60, 90 and 120 tetani/min) in AK1 deficient and wild type mice. This was done to have a range of energy demands in which to examine the role of AMPD in preserving muscle energy state. As a result of the limited AK activity, AMP deamination during the high energy demands of tetanic contractions was clearly limited as evidenced by markedly reduced IMP accumulation. Diminished AMPD capacity resulted in an increased accumulation of chemically measured ADP of approximately 0.90 µmol/g muscle weight above the resting ADP concentration. This would represent an increase in free ADP to ~1.5 mM, which is approximately 10 fold greater than what has been estimated to occur in muscle with normal AK activity (Fig. 3). Furthermore, this increase in ADP was verified as existing in the 'free,' non-bound form within the cell with 31P-NMR. This was the first report of a direct measurement of free ADP in intact skeletal muscle (60). As a result of this inordinate increase in ADP, the calculated energy from ATP hydrolysis was severely impaired (-46 and -53 kJ/mol) in muscles from AK deficient and WT muscles respectively (60, 61). Thus, these studies provide direct evidence that limited AMPD capacity can result in ADP accumulation during extreme energy demands of tetanic contractions.

Fig. 3. The initial rate of ADP accumulation in adenylate-1 knockout (AK-/-) and wild type mice. Adapted from Hancock et al., (61) with permission.

In addition to examining the metabolic impairment in AK deficient muscle, the muscle function was also assessed. As pointed out above, restoring resting cytoplasmic calcium concentrations following contraction is thought to be one of the most sensitive processes to reductions in energy availability. Furthermore, if the capacity of SERCA is sufficiently impaired, prolonged or absent muscle relaxation would be expected to occur. In AK deficient muscles that had ADP accumulation on the order of 1.5 mM a clear slowing of muscle relaxation was observed (Fig. 4). Additionally the impaired relaxation kinetics were only evident at the highest contraction frequencies examined (90 and 120 tetani/min). While relaxation kinetics were clearly delayed, near complete relaxation was evident and overall contractile function (force developed, rate of force development, and tension time integral) was remarkably resistant to the expected consequences of a reduced energy state and the high concentration of ADP.

Fig. 4. Loss of muscle force during intense contraction conditions (120 tetani/min; left panel) and a comparison of the contraction force profile between the first and 40th contraction in the sequence for adenylate-1 knockout (AK-/-) and wild type mice. The 40th contraction was selected since muscle [ADP] was elevated to ~1.5 mM during this time. Adapted from Hancock et al., (61) with permission.

The cost of maintaining the calcium gradient between the cytosolic and sarcoplasmic reticulum is defined by the relationship -2RT ln ([Ca2+]sr/[Ca2+]cyt). Given the cytosolic calcium concentration (50-100 nM) is roughly one ten thousandth of the calcium concentration in the SR (~1 mM), then the minimum energy required to maintain this gradient is -51 to -48 kJ/mol. The increase in ADP in AK deficient muscle, and the resulting challenge to the energy available from ATP (-46 kJ/mol) would be expected to severely impair the capacity for calcium sequestration (49, 50, 53). While relaxation was delayed, muscle contracture due to the inability of SERCA to sequester calcium did not occur. One possible explanation for this may be that the energy available was sufficient to achieve cytosolic calcium concentration that was markedly higher than resting concentrations but low enough where significant force production did not occur. For example, a calcium concentration of 250 nM would not likely cause much force production (63) and the energy required to achieve this cytosolic calcium concentration (assuming an [Ca2+]sr of 1 mM) would be -43 kJ/mol. Thus, sufficient energy exists to restore calcium to levels near the threshold concentration for force generation even with the large ADP accumulation that occurs in the absence of normal AK and AMPD activity. Another possible reason for the surprisingly robust muscle function in the context of such a large reduction in energy concerns the coupling efficiency of Ca2+/ATP by SERCA. The normal coupling of 2 Ca2+/ATP via SERCA may be reduced when the ADP concentration is markedly elevated. As mentioned above, a high concentration of ADP has been reported to cause calcium leak through SERCA (52). This would effectively reduce the free energy required to sequester each calcium ion, but increase the amount of ATP turnover by SERCA.

In conclusion, the high rates of ATP turnover possible in skeletal muscle can temporarily exceed the capacity for ATP synthesis causing a net reduction in ATP content. An inordinate accumulation of ADP is prevented when ATP depletion occurs via the AK and AMPD reactions, resulting in IMP accumulation that matches losses in ATP. By limiting ADP accumulation, AMPD and AK function to protect the cell from an excessive decline in the cellular energy state. If AMP deamination is prevented during intense contractions and leads to sufficient accumulation of ADP, there is expected to be a profound impact on muscle function. However, even in the context of ADP concentrations near 1.5 mM, representing a severe challenge to the energy state greater than previously observed, muscle function was remarkably well maintained. Thus, the protection of GATP may not be an essential role of AMPD in fast-twitch skeletal muscle. This potentially places a greater emphasis on the role of AMPD contributing to the retention of adenine nucleotide pool and amino acid deamination within skeletal muscle.

Acknowledgements: Cited work by the authors has been supported by NIH grants AR21617, AR43903. National Biomedical Research Institute grant MA00210, and Michigan State University grant IRPG 41006. C.R. Hancock is currently in the Department of Medicine, Washington University School of Medicine, St. Louis, MO, supported by NIH grant T32 AG000078. J.J. Brault is currently in the Department of Cell Biology, Harvard Medical School, Boston, MA, supported by a National Space Biomedical Research Institute grant.


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