Skeletal muscle creatine kinase

Rhabdomyolysis occurred in subjects with isoniazid poisoning in a retrospective analysis of 270 patients seen over a 5-year period at the PhUlipine General Hospital in Manilla (42). Skeletal muscle creatine kinase activity was raised in 31 of the 52 evaluable subjects who had taken more than 2.4 g/day of isoniazid. Creatine kinase activity peaked on days 5-6 and fell thereafter. Two patients developed acute renal insufficiency and required dialysis. Seizures occurred in all patients, and their duration, but not their frequency, correlated with raised creatine kinase activity. However, it is likely that factors other than seizures contribute to rhabdomyolysis in patients with isoniazid poisoning. 

Figure 12-14. The creatine phosphate shuttle of heart and skeletal muscle. The shuttle allows rapid transport of high-energy phosphate from the mitochondrial matrix into the cytosol. CKg, creatine kinase concerned with large requirements for ATP, eg, muscular contraction CIC, creatine kinase for maintaining equilibrium between creatine and creatine phosphate and ATP/ADP CKg, creatine kinase coupling glycolysis to creatine phosphate synthesis CK, , mitochondrial creatine kinase mediating creatine phosphate production from ATP formed in oxidative phosphorylation P, pore protein in outer mitochondrial membrane.

Creatine kinase, creatine kinase myocardial band Creatine kinase (CK) enzymes are found in many isoforms, with varying concentrations depending on the type of tissue. Creatine kinase is a general term used to describe the nonspecific total release of all types of CK, including that found in skeletal muscle (MM), brain (BB) and heart (MB). CK MB is released into the blood from necrotic myocytes in response to infarction and is a useful laboratory test for diagnosing myocardial infarction. If the total CK is elevated, then the relative index (RI), or fraction of the total that is composed of CK MB, is calculated as follows RI = (CK MB/CK total) x 100. An RI greater than 2 is typically diagnostic of infarction. 

The same reaction was recently proposed to detect creatine kinase (CK), an enzyme of high clinical significance in relation to the investigation of skeletal muscle disease and the diagnosis of myocardial infarct or cerebrovascular accidents. As ATP is a reaction product obtained from the reaction of ADP with creatine phosphate catalyzed by CK, this enzyme can be indirectly measured by the CL intensity read from the subsequent reaction of ATP with luciferin. Using the technique of electrophoretically mediated microanalysis (EMMA), it is possible to detect the enzyme using nanoliter volumes of biological sample with an improved speed and simplicity with respect to a conventional colorimetric method [100],... 

The enzyme creatine kinase (CK) is formed of two subunits that can either be of the brain (B) type or the muscle (M) type, and different combinations of these types lead to isozymes that predominate in the brain (BB), skeletal muscle (MM), and heart muscle (MB). 

In the course of studying the mechanism of action of creatine kinase from rabbit skeletal muscle (M.M isoenzyme), Kenyon and coworkers (4,90) have been involved in the design of specific irreversible inhibitors that are active-site-directed (affinity labels). Creatine kinase catalyzes the reversible transfer of a phosphoryl group ( the elements of "POi") from ATP to creatine, as shown in the following reaction ... 

Minor increases in creatine kinase (CK) activity in plasma are observed in some patients receiving reductase inhibitors, frequently associated with heavy physical activity. Rarely, patients may have marked elevations in CK activity, often accompanied by generalized discomfort or weakness in skeletal muscles. If the drug is not discontinued, myoglobinuria can occur, leading to renal injury. Myopathy may occur with monotherapy, but there is an increased incidence in patients... 

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. 

Hershenson, S. Helmers, N. Desmueles, P. Stroud, R. Purification and crystallization of creatine kinase from rabbit skeletal muscle. J. Biol. Chem., 261, 3732-3736 (1986)... 

Vaidya, H. Dietzler, D.N. Leykam, J.R Ladenson, J.H. Purification of five creatine kinase-MM variants from human heart and skeletal muscle. Biochim. Biophys. Acta, 790, 230-237 (1984)... 

Takasawa, T. Onodera, M. Shiokawa, H. Properties of three creatine kinases MM from porcine skeletal muscle. J. Biochem., 93, 389-395 (1983)... 

Gregor, M. Janovska, A. Stefl, B. Zurmanova, J. Mejsnar, J. Substrate channelling in a creatine kinase system of rat skeletal muscle under various pH conditions. Exp. Physiol., 88, 1-6 (2003)... 

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... 

Reasons for the presence of enzymes in the plasma Enzymes can normally be found in the plasma either because they were specifically secreted to fulfill a function in the blood, or because they were released by dead or damaged cells. Many diseases that cause tissue damage result in an increased release of intracellular enzymes into the plasma. The activities of many of these enzymes (for example, creatine kinase, lactate dehydrogenase, and alanine aminotransferase) are routinely determined for diagnostic purposes in diseases of the heart, liver, skeletal muscle, and other tissues. 

Brazeau, GA. and Fung, H.-L. Mechanisms of creatine kinase release from isolated rat skeletal muscles damaged by propylene glycol and ethanblRharm. Sci, 79, 393-397, May 1990. 

Brazeau, G.A, Natts, S.S, and Mathews, L.S. Role of calcium and arachidonic acid metabolites in creatine kinase release from isolated rat skeletal muscles damaged by organic cosjbl Ftemte)t. 

Creatine kinase (CK) is a dimeric enzyme with two subunits, M (muscle type) and B (brain type). Three isozymes are distinguished CK 1-BB (brain), CK 2-MB (heart), and CK 3-MM (skeletal muscle). The total CK activity found in skeletal muscle is almost entirely of the CK 3 type, that in heart muscle is 15-20% CK 2 and the remainder CK 3, and that in brain is all CK 1. In the human being, the only significant source of blood CK 2 is the heart muscle. Because the intact blood-brain barrier appears to be impermeable to CK, the occurrence of CK 1 in blood is unlikely. The total serum CK activity in healthy individuals is almost exclusively that of CK 3. 

The patient, a 63-year-old Caucasian female, was hospitalized on 4 April 2002 though 10 April 2002 for a non-ST segment elevation myocardial infarction (non-Q-wave MI per chart documentation). She had a negative adenosine stress test after the initial event. Her serum cardiac-specific troponin I (cTnl) concentration 24 hours after her onset of chest pain was 1.4 pg/L (upper limit of normal is 0.3 ng/mL), and her creatine kinase (CK) MB level was 12.5 pg/L (upper limit of normal 6.0 ng/mL). Three days post-event her cTnl level was 0.5 pg/L and her CK-MB level was 4.5 pg/L (Fig. 5-1). MB refers to one of the isoenzyme forms of CK found in serum. The form of the enzyme that occurs in brain (BB) does not usually get past the blood-brain barrier and therefore is not normally present in the serum. The MM and MB forms account for almost all of the CK in serum. Skeletal muscle contains mainly MM, with less than 2% of its CK in the MB form. MM is also the predominant myocardial creatine kinase and MB accounts for 10%-20% of creatine kinase in heart muscle. 

The procedure can be complemented by measuring the creatine-kinase MM (CK-MM) in the blood serum of the test animals. CK-MM is the muscle-specific enzyme which leaks out of a skeletal muscle if muscle damage has occurred. Determination of CK-MM should be conducted in the blood serum 24 hours after administration. 

Creatine kinase (CK) occurs in high concentrations in the brain, cardiac and skeletal muscle and is elevated in the blood with muscle damage. A rise in CK is seen in acute myocardial infarction but also in other conditions. A more specific marker is creatine kinase MB (CK-MB), which is an isoenzyme of creatine kinase that is more specific for cardiac muscle damage. CK or CK-MB will rise approximately 4 hours after an acute cardiac event and will reach a peak after approximately 24 hours and will remain raised for 3-4 days. 

Although it is true that abnormal proteins increase with age, most of them are a result of posttranslational changes. An example is the various isoforms of creatine kinase (CK). Here, the major isoenzyme, CK-MM (isoform CK-33), is normally synthesized in the heart and skeletal muscle. However, after its release into the circulation, carboxypeptidase hydrolyzes the terminal lysine from one of the M-peptides to form CK-32. Subsequent hydrolysis of the terminal lysine from the second M-peptide produces the third isoform, CK-3i (W8). Numerous similar posttranslational proteins are produced. Hence, the presence of abnormal proteins per se does not support this aging theory. 

Creatine kinase is a protein necessary for ATP generation. One of its forms, CK-MB, is found mainly in the myocardium and upon tissue damage, such as myocardial infarction (Ml), becomes elevated. It takes up to 24 h for the elevated level to reach its peak. A difficulty resides in the fact that unlike troponin, an assay does not allow us to distinguish between cardiac and skeletal muscle damage. Also, in about a third of Ml cases while CK-MB levels stay neutral, troponin elevation is noted. The normal level of troponin in the blood is less than 0.3 pg/1 while for CK-MB it is less than 3.0 ng/ml. For humans, the CK is in the range of 55-170 lU/1 (international units per liter) and is less specific than CK-MB for cardiac tissue damage. 

The creatine synthesized in the liver is transported through the bloodstream to skeletal and heart muscle. It enters the mitochondria, where it is phosphorylated to crealine-P Creatine kinase catalyzes this reversible addition of a phosphate group, as shown in Figure 4.34. Creatine-P is unique in that its only known function is as an energy buffer. The creatine P formed in the mitochondria travels to the contractile proteins in the cytoplasm of the muscle fiber. The polymer, or complex, of contractile proteins is called a myofibril. Contraction of a myofibril is coupled to the hydrolysis of ATP to ADP. The immediate replenishment of ATP is catalyzed by a second creatine kinase, residing on the myofibril, that catalyzes the conversion of creatine-P to creatine. This reversal of the reaction takes place in the... 

Likewise, following the repeated infusion of doses of 1000-2000 mg/kg DCLHb daily for 7 days or of 400 mg/kg every 6h for 3 days, the concentrations of AST, lactate dehydrogenase (LDH) and creatine kinase (CK) were elevated in monkeys. Isoenzyme profiles for CK and LDH revealed predominant increases in the MM form of CK and the LD-5 form of LDH. The MM-CK originates predominantly from skeletal muscle and may also derive from the myocardium however, the MB isoenzyme, which emanates only from myocardium, was not elevated. The elevation of LD-5 was also consistent with a skeletal muscle source. 

Aktas, M. Lefebvre, H.P. Toutain, P.-L. Braun, J.P. Disposition of creatine kinase activity in dog plasma following intravenous and intramuscular injection of skeletal muscle homogenates. J. Vet. Pharmacol. Ther. 1995, 18, 1-6. 

Tomlinson B, Cruickshank JM, Hayes Y, Renondin JC, Lui JB, Graham BR, Jones A, Lewis AD, Prichard BN. Selective beta-adrenoceptor partial agonist effects of pindolol and xamoterol on skeletal muscle assessed by plasma creatine kinase changes in healthy subjects. Br J Clin Pharmacol 1990 30(5) 665-72. 

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