School of Exercise and Rehabilitation Sciences, University of Toledo, 2801 W. Bancroft St., Toledo, OH 43606, USA.
Advanced Microscopy & Imaging Center, University of Toledo, Toledo, OH 43606, USA.
Int J Mol Sci. 2022 Jun 24;23(13):7028. doi: 10.3390/ijms23137028.
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.
受损骨骼肌的局部炎症环境通过在肌肉再生的初始阶段促进肌肉前体细胞的增殖，有助于损伤的恢复。然而，当新形成的（再生肌纤维）积累肌核并发生肥大时，炎症反应对再生后期的影响程度知之甚少。我们之前的工作表明，炎症分子 ICAM-1 通过涉及肌核定位和/或转录的过程促进再生肌纤维的肥大。本研究检验了以下假设：ICAM-1 通过增强定位于线性阵列（核链）中的肌核的转录活性，增强再生肌纤维中的整体转录。我们发现，与 ICAM-1-/- 小鼠相比，在损伤后 14 天和 28 天，野生型再生肌纤维中的转录水平高约 2 倍。这是因为在再生过程中，核链、核簇和外围位置的单个肌核的转录活性在野生型中比在 ICAM-1-/- 小鼠中高约 2 倍。ICAM-1 对核链中转录的增强似乎是肌纤维肥大的重要驱动因素，因为它与再生过程中肌纤维大小的增加呈统计学相关。总之，我们的发现表明，ICAM-1 通过增强肌核转录促进损伤后的肌纤维肥大。
