Muscle phosphocreatine

In the muscle, phosphocreatine and creatine undergo cyclisation to form creatinine (Figure 8.20(b)). Since creatinine cannot be metabohsed, it is released from muscle and is then excreted in the urine. This biochemical process is useful in clinical practice, since creatinine production is spontaneous and is remarkably constant 1.7% of the phosphocreatine and creatine in muscle cyclises each day, so that its concentration in blood provides an indication of the glomerular filtration rate, and hence provides an indication of the function (i.e. the health) of the kidney. 

In resting muscle phosphocreatine is present at at least five times the molar concentration of total adenine nucleotides and during contraction the creatine kinase reaction helps to maintain the intracellular concentration of ATP. 

Greenhaff, EL., K. Bodin, K. Soderlund, and E. Hultman, Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am J Physiol, 266 (Pt 1) E725-E730, 1994. 

Kehnder, M., J. Rico-Sanz, G. Kuhne, M. Dambach, R. Buchli, and U. Boutellier, Muscle phosphocreatine and glycogen concentrations in humans after creatine and glucose polymer supplementation measured noninvasively by 31P and 13C-MRS. Med Sci Sports Exerc, 30 S264, 1998. 

ATP stores in muscle are augmented or supplemented by stores of phosphocreatine. During periods of contraction, phosphocre-atine is hydrolyzed to drive the synthesis of needed ATP in the creatine kinase reaction ... 

Rigor ll a muscle condition in which muscle fibers, depleted of ATP and phosphocreatine, develop a state of extreme rigidity and cannot be easily extended. (In death, this state is called rigor mortis, the rigor of death.) From what you have learned about muscle contraction, explain the state of rigor in molecular terms. 

Le Rumeur, E., Le Moyec, L., Chagneau, F., Levasseur, M., Toulouse, P., Le Bars, R., De Certaines, J. (1989). Phosphocreatine and pH recovery without restoration of mechanical function during prolonged activity of rat gastrocnemius muscle An in vivo P NMR study. Arch. Int. Physiol. Biochem. 97,381-388. 

Striated muscle is composed of multinucleated muscle fiber cells surrounded by an electrically excitable plasma membrane, the sarcolemma. An individual muscle fiber cell, which may extend the entire length of the muscle, contains a bundle of many myofibrils arranged in parallel, embedded in intracellular fluid termed sarcoplasm. Within this fluid is contained glycogen, the high-energy compounds ATP and phosphocreatine, and the enzymes of glycolysis. 

Skeletal muscle contains phosphocreatine, which acts as an energy store for short-term (seconds) demands. 

In vivo, patients treated with AZT develop a mitochondrial myopathy with mitochondrial DNA depletion, deficiency of cytochrome c oxidase (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion (Lewis and Dalakas 1995 Dalakas 2001). Clinically, the patient presents with fatigue, myalgia, muscle weakness, wasting and elevated serum creatine kinase. Muscle biopsy shows ragged red fibers , the characteristic histopathologic changes of mitochondrial myopathy, cansed by subsarcolemmal accumulation of mitochondria (Lewis and Dalakas 1995). 

In contrast to the water resonance, Cr3 did not show a considerable MT effect in the water suppressed spectra resulting in MTRcr lower than 1%. Significant MT effects on the creatine/phosphocreatine signal in skeletal muscle have exclusively been described in rats. ... 

The synthesis of creatine. In the kidney, guanidinoace-tate is produced from arginine and glycine, then released into the blood to be taken up by the liver and methylated to form creatine (Figure 8.20(a)). The creatine is, in turn, taken up by the muscle where it is phosphorylated to produce phosphocreatine, which can maintain the ATP level, especially in explosive exercise. Creatine and phosphocreatine are converted in muscle to creatinine, which is important in clinical practice (Figure 8.20(b)) (Box 8.3). 

Figure 8.20 (a) The synthesis of phosphocreatine. The compound guanidinoacetate is formed from arginine and glycine in the kidney and is then transported to the liver where it is methylated addition of CHj (see Chapter 15) to form creatine (see Appendix 8.4 for details). Creatine is taken up by tissues/ organs/cells and phosphorylated to form phosphocreatine, particularly in muscle, (b) Conversion of phosphocreatine and creatine to creatinine in muscle. Creatinine is gradually formed and then released into blood and excreted in urine. 

In addition to the processes described above, there still remains one further process which, at least in some cells or tissues, is required prior to the utilisation of ATP in the cytosol that is, the transport of energy within the cytosol, via a shuttle. The transport of ATP out and ADP into the mitochondrion, via the translocase, results in a high ATP/ ADP concentration ratio in the cytosol. However, a high ratio means that the actual concentration of ADP in the cytosol is low, which could result in slow diffusion of ADP from a site of ATP utilisation back to the inner mitochondrial membrane. If sufficiently slow, it could limit the rate of ATP generation. To overcome this, a process exists that transports energy within the cytosol, not by diffusion of ATP and ADP, but by the diffusion of phosphocreatine and creatine, a process known as the phosphocreatine/creatine shuttle. The reactions involved in the shuttle in muscle help to explain the significance of the process. They are ... 

The phosphocreatine diffuses to the site of ATP utilisation (i.e. the myofibrils in skeletal muscle). 

Figure 9.20 The creatine/phosphocreatine shuttle between subsarcolemmal mitochondria and myosin ATPase in muscle. The distance between the mitochondria that reside just below the plasma membrane (sarcolemma) and the myofibrils in which the myosin ATPase results in contraction, is long in such muscles. The advantage of the position of these mitochondria is ready access to oxygen and fuel from blood. Such mitochondria are common in endurance athletes.

A variety of fuels are available to generate ATP for muscle activity phosphocreatine glycogen (which can be converted to lactic acid or completely oxidised to CO2) glucose (from liver glycogen, transported to the muscle via the blood and completely oxidised to CO2) triacylglycerol within the muscle (completely oxidised to CO2) and fatty acids from triacylglycerol in adipose tissue (completely oxidised to CO2). 

Table 13.11 Content of glycogen and concentration of phosphocreatine, ATP and Lactate in muscle before and after sprinting/ strength training exercises...

Figure 13.22 The decrease in phosphocreatine concentration in the muscle during stimulation. Electrical stimulation of muscle in the laboratory is used to mimic sprinting activity in the muscle. Data from Hultman Sjoholm (1983). The units for the concentration of phosphocreatine are pmole per gram dry weight of muscle taken by biopsy. Note apparent differences in concentration when data are presented as wet or dry weight.

Table 13.12 Effect of different types of physical activity on contents of glycogen and concentrations of phosphocreatine, ATP, ADP, phosphate and lactate, and on the pH in muscle at exhaustion...

In (a) the sprint, and middle-distance running there is little change in the glycogen content but a marked decrease in that of phosphocreatine and a marked increase in that of phosphate and a decrease in pH. The precise and relevant concentration of ADP in muscle is not easy to measure, since most of it is bound. Hence the data are not presented but the concentration can be calculated from the change in phosphocreatine concentration. This indicates that the decrease in the ATP/ADP ratio is tenfold. 

The enzyme preferentially acts on adenine nucleotide, and the equilibrium constant for the reaction in the direction written above is approximately 40, depending on magnesium ion and proton concentrations. The enzyme is inhibited by 20 mM chloride ion. Typically, one uses 1 -2 international units of the rabbit muscle enzyme along with 10 mM phosphocreatine. 

R. Esterhammer, M. Schocke, O. Gorny, L. Posch, H. Messner, W. Haschke, G. Praedrich and A. Greiner, Phosphocreatine kinetics in the calf muscle of patients with bilateral symptomatic peripheral arterial disease during exhaustive incremental exercise. Mol. Imaging Biol, 2008,10,30-39. 

Creatine (Cr) plays an important role in energy transmission and storage in cells and tissues with high energy demands. Tissues like the brain, retina, spermatozoa and cardiac and skeletal muscle contain the enzyme Cr kinase, which catalyses the interconversion of Cr and its phosphorylated analogue, phosphocreatine. The dephosphorylation of phosphocreatine yields energy, as ADP is simultaneously converted into ATP. 

Phosphocreatine (Fig. 13-5), also called creatine phosphate, serves as a ready source of phosphoryl groups for the quick synthesis of ATP from ADP. The phosphocreatine (PCr) concentration in skeletal muscle is approximately 30 nra, nearly ten times the concentration of ATP, and in other tissues such as smooth muscle, brain, and kidney [PCr] is 5 to 10 mM. The enzyme creatine kinase catalyzes the reversible reaction... 

Phosphocreatine, derived from creatine, is an important energy buffer in skeletal muscle (see Fig. 13-5). Creatine is synthesized from glycine and arginine (Fig. 22-26) methionine, in the form of S-adenosylmethionine, acts as methyl group donor. 

FIGURE 23-17 Energy sources for muscle contraction. Different fuels are used for ATP synthesis during bursts of heavy activity and during light activity or rest. Phosphocreatine can rapidly supply ATP. 

ATP and Phosphocreatine as Sources of Energy for Muscle During muscle contraction, the concentration of phosphocreatine in skeletal muscle drops while the concentration of ATP remains fairly constant. However, in a classic experiment, Robert Davies found that if he first treated muscle with l-fluoro-2,4-dinitrobenzene (p. 97), the concentration of ATP declined rapidly while the concentration of phosphocreatine remained unchanged during a series of contractions. Suggest an explanation. 

Creatine phosphate (also called phosphocreatine), the phosphory-lated derivative of creatine found in muscle, is a high-energy compound that can reversibly donate a phosphate group to ADP to form ATP (Figure 21.16). Creatine phosphate provides a small but rapidly mobilized reserve of high-energy phosphates that can be used to maintain the intracellular level of ATP during the first few minutes of intense muscular contraction. [Note The amount of creatine phosphate in the body is proportional to the muscle mass.]... 

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