Genetic Variants in MCP1 and MCP1R are Associated with Markers of Muscle Damage

Abstract

PURPOSE: Understanding the genetic factors that underlie inflammation and muscle repair could have profound effects on improved therapeutics for pain relief. We hypothesized that single nucleotide polymorphisms (SNPs) in the gene MCP1, which is highly expressed in injured skeletal muscle and involved in the repair and functional recovery of the injured muscle, would be associated with markers of muscle damage. METHODS: We genotyped nine different SNPs in MCP1 and three SNPs in MCP1R in a group of 151 individuals who completed a bout of eccentric exercise (50 maximal eccentric contractions). The SNPs were examined with indicators of muscle damage [strength loss, muscle soreness, and increases in circulating levels of creatine kinase (CK) and myoglobin (Mb)] and maximum baseline isometric strength values. RESULTS: In females, two SNPs in MCP1 were associated with baseline CK levels: rs1026411 (AA: N=42; 73.7 ± 5.5 U/l vs. AG/GG: N=34; 99.7 ± 6.1 U/l, p=0.002), rs13900 (CC: N=42; 73.9 ± 5.4 U/L vs. AG/GG: N=35; 98.9 ± 6.0 U/l, p = 0.003), and a SNP in MCP1R rs1799865 (TT: N=36; 94.7 ± 6.1 U/l vs. CT/CC: N=41; 77.0 ± 5.7 U/l, p = 0.03). In addition, females with a copy of the C allele for rs3918358 in MCP1R had higher myoglobin values four days post-exercise (AA: N=33; 237.8 ± 64.7 ng/ml vs. AC/CC: N=43; 165.3 ± 17.0 ng/ml, p = 0.04) and greater maximum strength loss (AA: N=34; −12.2 ± kg vs. AC/CC: N=43; −24.3 ± kg, p = 0.04). In the MCP1R gene, males with a copy of the rare allele for two SNPs had higher values of myoglobin seven days post-exercise for rs3918358 (AA: N=33; 85.0 ± 19.3 ng/ml vs. AC/CC: N=38; 159.8 ± 18.0 ng/ml, p = 0.007) and rs1799865 (TT: N=32; 76.4 ± 19.0 ng/ml vs. TC/CC: N=40; 165.3 ± 17.0 ng/ml, p = 0.001). In addition, males showed a differences in average baseline strength for rs3918358 (AA: N=33; 119.8 ± 4.8 kg vs. AC/CC: N=41; 106.7 ± 4.2 kg, p = 0.001; p = 0.04. CONCLUSIONS: We have discovered variants in the MCP1 and MCP1R genes that affect measures of muscle damage (muscle soreness, isometric strength, myoglobin, and CK) after a bout of strenuous eccentric exercise. Baseline CK and strength were also affected in a sex-dependent manner. These data suggest that these SNPs affect MCP1 RNA or protein levels, which could modify signaling between macrophages and satellite cells, promoting or hindering repair during the recovery period.