Strenuous exercise results in damage to skeletal muscle that is manifested in delayed muscle pain, prolonged strength loss, and increases in muscle proteins in the blood, especially creatine kinase (CK) and myoglobin (Mb). Some individuals experience profound changes in these variables in response to standard laboratory exercise or recreational activities. We proposed that variations in genes coding for two myofibrillar proteins [alpha-actinin 3 (ACTN3) and myosin light chain kinase (MLCK)] may explain the large variability in the response to muscle-damaging exercise. We hypothesized that subjects with specific single nucleotide polymorphisms (SNPs) in ACTN3 and MLCK would show a greater loss in muscle strength and/or a greater increase in blood CK and Mb in response to eccentric exercise. Blood from 157 subjects who performed a standard elbow flexion eccentric exercise protocol was tested for association between genotypes of ACTN3 (1 SNP tested: R577X) and MLCK (2 SNPs tested: C49T and C37885A) and changes in blood CK and Mb and isometric strength. Subjects possessing the ACTN3-deficient genotype (XX) had lower baseline CK compared with the heterozygotes (P = 0.035). After the eccentric exercise, those subjects homozygous for the MLCK 49T rare allele had a significantly greater increase in CK and Mb (P < 0.01) compared with the heterozygotes, and those heterozygous for MLCK C37885A had a significantly greater increase in CK compared with the homozygous wild type (P < 0.05). There was only one subject homozygous for the rare MLCK 37885A allele. MLCK C37885A was also associated with postexercise strength loss (P < 0.05); the heterozygotes demonstrated greater strength loss compared with the homozygous wild type (CC). These results show that variations in genes coding for specific myofibrillar proteins influence phenotypic responses to muscle damaging exercise.

Exertional muscle damage produced by eccentric exercise in healthy individuals can cause profound CK and Mb elevations without renal impairment.

In response to eccentric exercise, women experienced greater immediate strength loss than men and were more likely to be high responders for immediate strength loss; men experienced greater serum CK activity than women and were more likely to be high responders for increased serum CK. Although the explanation for high responders to eccentric exercise remains unknown, we have shown that there are sex-specific differences in CK and strength-loss response after eccentric exercise.

Novel eccentric (lengthening contraction) exercise typically results in muscle damage, which manifests as prolonged muscle dysfunction, delayed onset muscle soreness, and leakage of muscle proteins into circulation. There is a large degree of variability in the damage response of individuals to eccentric exercise, with higher responders at risk for potentially fatal rhabdomyolysis. We hypothesized that single nucleotide polymorphisms (SNPs) in chemokine ligand 2 (CCL2) and its receptor chemokine receptor 2 (CCR2) associate with the high degrees of variability in the muscle damage response. We based this hypothesis on CCL2's roles in macrophage and satellite cell signaling in injured muscle. DNA was obtained from 157 untrained men and women following maximal eccentric exercise. Strength loss, soreness, serum creatine kinase (CK), and myoglobin levels before and during recovery from a single exercise bout were tested for association with 16 SNPs in CCL2 and CCR2. The rare alleles for rs768539 and rs3918358 (CCR2) were significantly (P<0.05) associated with lower preexercise strength in men, whereas CCL2 SNPs (rs13900, rs1024611, and rs1860189) and CCR2 (rs1799865) were associated with altered preexercise CK levels in women. During recovery, the rs3917878 genotype (CCL2) was associated with attenuated strength recovery in men and an elevated CK response in women. CCR2 variants were associated with slower strength recovery in women (rs3918358) and elevated soreness (rs1799865) across all subjects. In summary, we found that SNPs in CCL2 and CCR2 are associated with exercise-induced muscle damage and that the presence of certain variants may result in an exaggerated damage response to strenuous exercise.

We examined the association of a novel single-nucleotide polymorphism (SNP) in IGF-I (IGF-I -C1245T located in the promoter) and eight SNPs in the IGF-II gene region with indicators of muscle damage [strength loss, muscle soreness, and increases in circulating levels of creatine kinase (CK) and myoglobin] after eccentric exercise. We also examined two SNPs in the IGF binding protein-3 (IGFBP-3). The age, height, and body mass of the 151 subjects studied were 24.1 +/- 5.2 yr, 170.8 +/- 9.9 cm, and 73.3 +/- 17.0 kg, respectively. There were no significant associations of phenotypes with IGF-I. IGF-II SNP (G12655A, rs3213216) and IGFBP-3 SNP (A8618T, rs6670) were not significantly associated with any variable. The most significant finding in this study was that for men, IGF-II (C13790G, rs3213221), IGF-II (ApaI, G17200A, rs680), IGF-II antisense (IGF2AS) (G11711T, rs7924316), and IGFBP-3 (-C1592A, rs2132570) were significantly associated with muscle damage indicators. We found that men who were 1) homozygous for the rare IGF-II C13790G allele and rare allele for the ApaI (G17200A) SNP demonstrated the greatest strength loss immediately after exercise, greatest soreness, and highest postexercise serum CK activity; 2) homozygous wild type for IGF2AS (G11711T, rs7924316) had the greatest strength loss and most muscle soreness; and 3) homozygous wild type for the IGF2AS G11711T SNP showed the greatest strength loss, highest muscle soreness, and greater CK and myoglobin response to exercise. In women, fewer significant associations appeared.