Discussion
The results of the current meta-analysis, performed on 25 treatment arms, showed advantageous effects of creatine consumption in reduction of CK and LDH concentration after different follow-ups after exercise.
Muscle Damage is a phenomenon that may happen because of several reasons, like cell necrosis or rupture, including about 10 to 55 percent of total muscular injuries (43). The muscle damage can be determined as the plasma membrane disruption, accompanied by the muscle proteins loss (i.e. CK, LDH and myoglobin), increased inflammatory cells crowd in the muscle fibers (i.e. neutrophils and macrophages), influx of serum proteins, DOMS, functional impairment (week performance and loss of strength), and some structural disorders like sarcomere Z lines disarrangement (7, 44).
The present meta analysis evaluated indirect muscle damage indices, including CK and LDH among trained and untrained both sexes individuals, looking at reported articles. Proteins like CK and LDH have been extensively applied as markers of muscle micro-damages (45) and usually has been evaluated to be an indirect biomarkers of post exercise muscle damage due to their easiness of identification and the relatively low cost of tests to quantify it (46, 47). In spite of CK and LDH rising post exercise being much variable and affected by exercise variable and individual factors, the assessment of CK and LDH pre- and post-exercise may provide a diagnostic tool for the detection of post-exercise muscle damage, with much less invasiveness than needed in a muscle biopsy (48).
Wide assays has assessed the creatine consumption effects on performance in exercise (12). However, a few surveys have assessed the effect of creatine consumption on muscle recovery post exercise damage (49, 50). Willoughby and Rosene (51) have indicated that by ongoing creatine consumption post exercise, creatine may operate as a gene transcription co-regulator of amino acid pools, therefore increasing synthesis of myofibrillar protein during recovery after exersice (52).
Almost 95 percent of creatine is accumulated in skeletal muscles while the remained 5 percent is stored the brain, testes and heart (53, 54). Of this, about 60 percent of creatine is accumulated as phosphocreatine with the remaining creatine containing the free creatine pool (55). Creatine consumption (e.g. 20 g/day for 5 days) has been reported to enhance phosphocreatine and muscle free creatine usually by 15 to 40 percent (56). It is indicated that creatine, can bind to the plasma membrane due to amphipathic nature, therewith increasing membrane stability and decrease CK and LDH loss (57).
In the current meta-analysis the positive effects of creatine could cause decrease in CK concentration overall, regardless of subgroup analysis, while being non-significant in LDH. Subgroup analysis showed the creatine supplementation effect on lowering serum CK is significant in 48, 72 and 96 hours follow-ups after exercise. But due to high heterogeneity of the data to our knowledge these results should not be considered reliable. Also, creatine consumption reduce LDH significantly in 48 hours follow-ups after exercise and there was no considerable heterogeneity between trials. CK and LDH responses might depend on when the initial muscle damage happened, the training status of the individuals and the orientation with the physical activity applied (58), and thus the limit of myocellular specific proteins release. In this regard, trials with untrained participants had a significant decrease in CK concentrations with creatine supplementation.
According to expectations, dose of >20 g/day creatine had significant effect on lowering CK. But contrary to expectations trials with creatine supplementation duration of less than one week had significant lower CK concentration. It can be speculated that participant in all 8 trials (2 studies) that used >20 g/day creatine, conducted with duration of less than one week (31, 39). Above-mentioned subgroup analysis indicated that dose of creatine supplementation is more important than duration of supplementation for decreased CK concentration.
Weight gain is the only side effect that has been suggested which may be a desirable effect for many patient populations and athletes (59-61). Contrary to this safety, worries have been increased in scientific community and media related to the creatine consumption (62-64). In this case worries have been increased that consumption of creatine may elevate chronically creatine synthesis suppression, promote muscle, liver and renal damage, alter electrolyte situation and lead to long-term side effects (63, 65, 66). Moreover, creatine has been reported to cause dehydration, diarrhea, promote cramping and increase gastrointestinal upset (67-69).
The present meta-analysis had several limitations. No included studies in this meta-analysis blinded the providers/ assessors and only one study blinded the participants. Due to the nature of physical activity interventions, blinding in such studies may be challenging. Moreover, evidence was downgraded due to the lack of homogeneity among included articles and subgroup hypothesis were not sufficient for founding the source of heterogeneity. However, follow-ups after exercise explained potential between-study heterogeneity, especially for LDH concentration. Lack of information about data on intensity and frequency of exercise, genetic background, lifestyle factors and lack of complete baseline CK and LDH data for subgroup analysis make overall interpretation of the results difficult. Further, a significant gender affect was suggested in activity of serum CK concentration in other investigations (70). Many factors can influence the high heterogeneity stated.
The main strengths of the current meta-analysis are evaluation of <24, 24, 48, 72 and 96 hours follow-ups measurement of muscle damage indices after exercise and subgroup analysis based on follow-ups, the dose of supplementation, trial duration and train status of individuals on the overall effect sizes. The second one, we endeavored to minimize any biases in this meta-analysis procedure by conducting a comprehensive search of the databases as well as performing and describing the results using the PRISMA guidelines.