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Creatine phosphokinase (CPK), also known as creatine kinase (CK), is the enzyme that catalyzes the reaction of creatine and adenosine triphosphate (ATP) to phosphocreatine (PCr) and adenosine diphosphate (ADP).[1] This CK enzyme reaction is reversible; ATP can be generated from PCr and ADP. The phosphocreatine created from this reaction is used to supply tissues and cells that require substantial amounts of ATP, like the brain, skeletal muscles, and the heart.[2] CK is a central regulator of cellular energy homeostasis. Many conditions can cause derangement in CK levels, including rhabdomyolysis, heart disease, kidney disease, or medications.[3] As such, it is a diagnostic indicator for specifically rhabdomyolysis and acute myocardial infarction (AMI), among other medical disorders.

Creatine kinase (CK) is a compact enzyme of around 82 kDa found in both the cytosol and mitochondria of tissues with high energy demands.[4] In the cytosol, CK comprises 2 polypeptide subunits of around 42 kDa, and 2 subunits are found: M (muscle type) and B (brain type).[5] The genes for these subunits are located on different chromosomes: B on 14q32 and M on 19q13. These subunits allow the formation of 3 tissue-specific isoenzymes: CPK-MB (cardiac muscle), CPK-MM (skeletal muscle), and CPK-BB (brain). Typically, the ratio of subunits varies with muscle type: skeletal muscle (98% MM to 2% MB), cardiac muscle (70% to 80% MM and 20% to 30% MB), while the brain predominantly has the isoenzyme BB.[6] In mitochondria, 2 specific forms of CK exist: Mt-CK, a non-sarcomeric type called ubiquitous Mt-CK expressed in various tissues such as the brain, smooth muscle, and sperm, and a sarcomeric Mt-CK expressed in cardiac and skeletal muscle. The mitochondrial CK isoform is an octamer consisting of 4 dimers each.[7] While mitochondrial CK is directly involved in forming PCr from mitochondrial ATP, cytosolic CK regenerates ATP from ADP using PCr. This happens at intracellular sites where ATP is used in the cell, with CK acting as an in situ ATP regenerator. Mt-CK and cytosolic CK are connected in a so-called PCr/Cr-shuttle or circuit.[8] PCr generated by Mt-CK in mitochondria is shuttled to cytosolic CK that is coupled to ATP-dependent processes, eg, ATPases, such as actomyosin ATPase and calcium ATPase involved in muscle contraction, and sodium/potassium ATPase involved in sodium retention in the kidney.[9] The bound cytosolic CK accepts PCr shuttled through the cell and uses ADP to regenerate ATP, which the ATPases use as an energy source (CK is associated with the ATPases, forming a coupled microcompartment).[10] PCr is a buffer and transporter between subcellular sites of energy production (mitochondria and glycolysis) and energy utilization (ATPases).[11]

Mt-CK and cytosolic CK are connected in a so-called PCr/Cr-shuttle or circuit.[8] PCr generated by Mt-CK in mitochondria is shuttled to cytosolic CK that is coupled to ATP-dependent processes, eg, ATPases, such as actomyosin ATPase and calcium ATPase involved in muscle contraction, and sodium/potassium ATPase involved in sodium retention in the kidney.[9] The bound cytosolic CK accepts PCr shuttled through the cell and uses ADP to regenerate ATP, which the ATPases use as an energy source (CK is associated with the ATPases, forming a coupled microcompartment).[10] PCr is a buffer and transporter between subcellular sites of energy production (mitochondria and glycolysis) and energy utilization (ATPases).[11] Typically, CK is available in heart tissue, skeletal muscles, the brain, etc. However, upon muscular injury, leakage of CK into the bloodstream occurs. Thus, CK is indicative of muscular damage. CPK-MB is a more specific indicator of myocardial muscle damage, while CPK-MM is more indicative of skeletal muscle damage.[12] CK activity in the serum of healthy people is almost exclusively due to MM activity (though small amounts of CPK-MB may be present) due to the physiological turnover of muscle tissue.[13] When electrophoresed, CPK-MM runs closest to the cathode, CPK-MB has intermediate mobility, and CPK-BB moves farthest from the point of application toward the anode. Mt-CK, which runs more cathodal than the MM fraction, is usually associated with tissue necrosis that accompanies severe anoxic shock and liver disease.[14] CK activity is also found in a macromolecular form—the so-called macro-CK. Macro-CK is transiently found in sera of up to 6% of hospitalized patients, but only a small proportion of these have increased CK activities in serum.[15] The enzyme exists in 2 forms, types 1 and 2. Macro-CK type 1 is a complex of CK, typically CK-BB, and an immunoglobulin, commonly IgG.[16] Macro-CK type 1 is usually seen in women aged older than 50. Macro-CK type 2 is oligomeric Mt-CK found in severely ill adults with malignancies or children with tissue distress.[17]

When electrophoresed, CPK-MM runs closest to the cathode, CPK-MB has intermediate mobility, and CPK-BB moves farthest from the point of application toward the anode. Mt-CK, which runs more cathodal than the MM fraction, is usually associated with tissue necrosis that accompanies severe anoxic shock and liver disease.[14] CK activity is also found in a macromolecular form—the so-called macro-CK. Macro-CK is transiently found in sera of up to 6% of hospitalized patients, but only a small proportion of these have increased CK activities in serum.[15] The enzyme exists in 2 forms, types 1 and 2. Macro-CK type 1 is a complex of CK, typically CK-BB, and an immunoglobulin, commonly IgG.[16] Macro-CK type 1 is usually seen in women aged older than 50. Macro-CK type 2 is oligomeric Mt-CK found in severely ill adults with malignancies or children with tissue distress.[17] Both M and B subunits have a C-terminal lysine residue, but only the former is hydrolyzed by the action of carboxypeptidases present in the blood. Carboxypeptidases B or N sequentially hydrolyze the lysine residues from CKMM to produce 2 CK-MM isoforms—CK-MM2 (1 lysine residue removed) and CK-MM1 (both lysine residues removed).[18] The loss of positively charged lysine produces a more negatively charged CK molecule with greater anodic mobility at electrophoresis. Because CK-MB has only 1 M subunit, the dimer coded by the M and B genes is CK-MB2, and the lysine-hydrolyzed dimer is CK-MB1. The assay of the CK isoforms requires special techniques, such as high-voltage electrophoresis (with gel cooling), HPLC, chromatofocusing, or immunoassay.[19]

Creatine phosphokinase (CPK) or creatine kinase (CK) is essential in diagnosing acute rhabdomyolysis or AMI and chronic conditions such as sickle cell disease. As such, several clinicians may provide their diagnostic interpretation of an individual patient. An interprofessional team consisting of a nephrologist, surgeon, and nurse may manage the condition in a patient who presents with rhabdomyolysis after an increased CK level. The nephrologist strives to improve kidney function in such patients, as acute kidney injury is the most common complication of rhabdomyolysis. The surgeon may need to surgically repair any damaged muscle or tissue that leads to the condition. The nurse should teach the patient about managing their condition and avoiding exacerbating or triggering rhabdomyolysis. The healthcare team can consult with the pharmacist to verify that any patient's medications are not potential sources for elevated CK.[88] Any hospital staff working in the emergency department should know that intravenous fluid therapy is started promptly to curb acute kidney injury in patients with suspected rhabdomyolysis.[89]