Polygenic mechanisms underpinning the response to exercise-induced muscle damage in humans: In vivo and in vitro evidence

J Cell Physiol. 2022 Jul;237(7):2862-2876. doi: 10.1002/jcp.30723. Epub 2022 Mar 21.


We investigated whether 20 candidate single nucleotide polymorphisms (SNPs) were associated with in vivo exercise-induced muscle damage (EIMD), and with an in vitro skeletal muscle stem cell wound healing assay. Sixty-five young, untrained Caucasian adults performed 120 maximal eccentric knee-extensions on an isokinetic dynamometer to induce EIMD. Maximal voluntary isometric/isokinetic knee-extensor torque, knee joint range of motion (ROM), muscle soreness, serum creatine kinase activity and interleukin-6 concentration were assessed before, directly after and 48 h after EIMD. Muscle stem cells were cultured from vastus lateralis biopsies from a separate cohort (n = 12), and markers of repair were measured in vitro. Participants were genotyped for all 20 SNPs using real-time PCR. Seven SNPs were associated with the response to EIMD, and these were used to calculate a total genotype score, which enabled participants to be segregated into three polygenic groups: 'preferential' (more 'protective' alleles), 'moderate', and 'non-preferential'. The non-preferential group was consistently weaker than the preferential group (1.93 ± 0.81 vs. 2.73 ± 0.59 N ∙ m/kg; P = 9.51 × 10-4 ) and demonstrated more muscle soreness (p = 0.011) and a larger decrease in knee joint ROM (p = 0.006) following EIMD. Two TTN-AS1 SNPs in linkage disequilibrium were associated with in vivo EIMD (rs3731749, p ≤ 0.005) and accelerated muscle stem cell migration into the artificial wound in vitro (rs1001238, p ≤ 0.006). Thus, we have identified a polygenic profile, linked with both muscle weakness and poorer recovery following EIMD. Moreover, we provide evidence for a novel TTN gene-cell-skeletal muscle mechanism that may help explain some of the interindividual variability in the response to EIMD.

Keywords: eccentric exercise; extracellular matrix (ECM); fibroblast; myoblast; single-nucleotide polymorphism (SNP); total genotype score (TGS).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Exercise* / physiology
  • Humans
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiology*
  • Myalgia* / genetics
  • Myalgia* / pathology
  • Polymorphism, Single Nucleotide
  • Quadriceps Muscle / cytology
  • Quadriceps Muscle / physiology
  • Stem Cells / cytology
  • Torque