1. Introduction

CK is a compact enzyme of around 82 kDa that is found in both the cytosol and mitochondria of tissues where energy demands are high. In the cytosol, CK is composed of two polypeptide subunits of around 42 kDa, and two types of subunit are found: M (muscle type) and B (brain type). These subunits allow the formation of three tissue-specific isoenzymes: CK-MB (cardiac muscle), CK-MM (skeletal muscle), and CK-BB (brain). Typically, the ratio of subunits varies with muscle type: skeletal muscle: 98% MM and 2% MB and cardiac muscle: 70–80% MM and 20–30% MB, while brain has predominantly BB. In mitochondria there are two specific forms of mitochondrial CK (Mt-CK): a nonsarcomeric type called ubiquitous Mt-CK expressed in various tissues such as brain, smooth muscle, and sperm, and a sarcomeric Mt-CK expressed in cardiac and skeletal muscle [1].

CK also occurs as macroenzymes. Macro-CK type 1 is a complex of CK (most often CK-BB) and immunoglobulin (most often IgG) and is typically greater than 200 kDa in size. Macro-CK type 2 is a polymer of Mt-CK with a molecular mass of greater than 300 kDa [2]. These forms of CK are expressed during disease and/or dysfunction, for example, macro-CK 1 is associated with cardiovascular and autoimmune disease and macro-CK 2 with cancer. CK catalyzes the reversible phosphorylation of creatine to phosphocreatine and of ADP to ATP [3, 4], and as such it is important in regeneration of cellular ATP:CK forms the core of an energy network known as the phosphocreatine (PCr) circuit (see Figure 1). In this circuit, the cytosol isoenzymes are closely coupled to glycolysis and produce ATP for muscle activity. The MtCK version is closely coupled to the electron transport chain and can use mitochondrial ATP to regenerate PCr, which readily returns to the cytosol to resupply cytosolic PCr. This shuttle system is critical for the production and maintenance of energy supply and is involved in the metabolic feedback regulation of respiration [5]. It is unsurprising, therefore, that skeletal muscle has high levels of CK that can account for as much as 20% of the soluble sarcoplasmic protein in specific muscles.

Figure 1: Phosphocreatine (PCr) circuit showing the rephosphorylation of creatine (Cr) in mitochondria using ATP derived from oxidative phosphorylation (oxid phos) and subsequent use of mitochondrial PCr by cytosolic creatine kinase (CK) to resupply ATP for muscle activity, adapted from Saks [5].

Until the mid-1990s, determination of serum CK levels was a key tool in the diagnosis of myocardial infarction (MI) in patients presenting with chest pain in emergency departments. Subsequently, the diagnostic role has been replaced, to a certain extent, by the muscle protein troponin. However, raised levels of serum CK are still closely associated with cell damage, muscle cell disruption, or disease. These cellular disturbances can cause CK to leak from cells into blood serum [6]. Measurement of serum CK activity and determination of isoenzyme profiles are still an important indicator of the occurrence of muscle cell necrosis and tissue damage due to disease or trauma [3].

There has been extensive discussion in the literature regarding the significance of raised levels of serum CK following physical exercise in relation to degrees of muscle cell damage or disturbance. While the reason for release of CK into the circulation is clear in cases such as MI, it is less clear why low- to moderate-intensity physical exercise should also result in release of CK into blood serum. It is certainly confusing that resistance training elicits the greatest release of CK and at the same time provides the best route for muscle hypertrophy. Myofibrillar CK-MM is bound to the M-line of the sarcoplasmic reticulum of myofibrils and is also found in the space of the I-band sarcomeres providing support for muscle energy requirements [7]. Thus, the enzyme is normally confined to the muscle cell so the question arises: do raised levels of CK following a period of exercise represent a degree of actual muscle damage and loss of muscle cell integrity, or is there some other molecular explanation that is not permanent cell damage, but a temporal disturbance or disruption to muscle processes? A greater understanding of this issue could have significant implications for exercise strategy and training programme design (performance and recovery). This is true, not only for athletic populations but also for individuals who participate in strenuous exercise as part of their lifestyle. In this paper, we examine current evidence and opinion relating to the release of CK from skeletal muscle tissue into blood serum in response to muscle exercise.