Intercellular Adhesion Molecule-1 Enhances Myonuclear Transcription during Injury-Induced Muscle Regeneration

The local inflammatory environment of injured skeletal muscle contributes to the resolution of the injury by promoting the proliferation of muscle precursor cells during the initial stage of muscle regeneration. However, little is known about the extent to which the inflammatory response influences the later stages of regeneration when newly formed (regenerating myofibers) are accumulating myonuclei and undergoing hypertrophy. Our prior work indicated that the inflammatory molecule ICAM-1 facilitates regenerating myofiber hypertrophy through a process involving myonuclear positioning and/or transcription. The present study tested the hypothesis that ICAM-1 enhances global transcription within regenerating myofibers by augmenting the transcriptional activity of myonuclei positioned in linear arrays (nuclear chains). We found that transcription in regenerating myofibers was ~2-fold higher in wild type compared with ICAM-1-/- mice at 14 and 28 days post-injury. This occurred because the transcriptional activity of individual myonuclei in nuclei chains, nuclear clusters, and a peripheral location were ~2-fold higher in wild type compared with ICAM-1-/- mice during regeneration. ICAM-1's enhancement of transcription in nuclear chains appears to be an important driver of myofiber hypertrophy as it was statistically associated with an increase in myofiber size during regeneration. Taken together, our findings indicate that ICAM-1 facilitates myofiber hypertrophy after injury by enhancing myonuclear transcription.