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To test the hypothesis that one or more genetic polymorphisms (Single Nucleotide Polymorphisms (SNPs)) confer a propensity for individuals to experience profoundly elevated blood levels of creatine kinase (CK) and myoglobin (Mb) in response to overexertion exercise.Blood samples were obtained from 181 individuals and analyzed for genomic DNA sequence. We tested for the presence of 12 SNPs in a total of 9 skeletal muscle genes. CK activity and Mb concentration were analyzed from blood samples before exercise and at 4, 7 and 10 days following 50 maximal eccentric (muscle lengthening) contractions of the elbow flexor muscles. Associations between genotype and CK activity and Mb concentration were tested by ANOVA. Subjects were instructed to maintain hydration throughout the study.Viable DNA was obtained for 157/181 subjects. The only SNP associated with increases in blood CK activity and Mb was myosin light chain kinase (MLCK) C49T. Genotype distribution for MLCK C49T was 63.4% CC, 32.7% CT and 3.9% TT. A significant association was found between MLCK C49T and CK activity (p<0.001) and Mb at 4 days post-exercise (p<0.05). For CC, CT and TT genotypes, CK values at 4 days post-exercise were 5641, 8693, and 29727 U/L, respectively - representing ∼34, 53, and 180 fold changes over baseline. Corresponding values for Mb were 317, 437, and 943 ng/ml, respectively - representing ∼ 12, 16, and 35 fold changes from baseline.Significant associations between MLCK C49T genotype and blood protein markers of exercise-induced muscle damage suggest that the response to overexertion exercise is, at least in part, modulated by genetic factors. Individuals possessing the MLCK C49T mutation appear more susceptible to profound increases in blood CK and Mb in a dose-dependent (presence of 1 or 2 “T” alleles) manner. Although these subjects did not show evidence of kidney dysfunction in the current study, it is likely that the co-presence of nephrotoxic factors (e.g. dehydration) could increase the risk of renal failure. Therefore, we conclude that the MLCK C49T mutation may dictate the susceptibility of individuals to clinically-relevant exertional rhabdomyolysis.