Positional Context of Myonuclear Transcription During Injury-Induced Muscle Regeneration

Abstract

Fundamental aspects underlying downstream processes of skeletal muscle regeneration, such as myonuclear positioning and transcription are poorly understood. This investigation begins to address deficiencies in knowledge by examining the kinetics of myonuclear accretion, positioning, and global transcription during injury-induced muscle regeneration in mice. We demonstrate that myonuclear accretion plateaus within 7 days of an injury and that the majority (∼70%) of myonuclei are centrally aligned in linear arrays (nuclear chains) throughout the course of regeneration. Relatively few myonuclei were found in a peripheral position (∼20%) or clustered (∼10%) together during regeneration. Importantly, transcriptional activity of individual myonuclei in nuclear chains was high, and greater than that of peripheral or clustered myonuclei. Transcription occurring primarily in nuclear chains elevated the collective transcriptional activity of regenerating myofibers during the later stage of regeneration. Importantly, the number of myonuclei in chains and their transcriptional activity were statistically correlated with an increase in myofiber size during regeneration. Our findings demonstrate the positional context of transcription during regeneration and highlight the importance of centralized nuclear chains in facilitating hypertrophy of regenerating myofibers after injury.

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

“…This premise is supported by positive correlations between myonuclear 2 of 17 number and regenerating myofiber size [5,7], as well as elevated levels of transcription in regenerating myofibers after injury [7]. A role of myonuclear positioning in the maturation of regenerating myofibers is indicated by the finding that the transcriptional activity of myonuclei in nuclear chains is notably higher than that of peripheral and clustered myonuclei [7]. Furthermore, the number of myonuclei in nuclear chains and the transcription occurring in nuclear chains are strong predictors of an increase in regenerating myofiber size after injury [7].…”

“…In theory, myonuclear accretion promotes hypertrophy of regenerating myofibers by increasing their capacity for transcription. This premise is supported by positive correlations between myonuclear 2 of 17 number and regenerating myofiber size [5,7], as well as elevated levels of transcription in regenerating myofibers after injury [7]. A role of myonuclear positioning in the maturation of regenerating myofibers is indicated by the finding that the transcriptional activity of myonuclei in nuclear chains is notably higher than that of peripheral and clustered myonuclei [7].…”

“…During regeneration, nascent (regenerating) myofibers accumulate hundreds of nuclei (myonuclei) that, strikingly, are found in distinctly different cytoplasmic positions [4][5][6]. The majority of myonuclei are situated in centralized linear arrays (nuclear chains) [4,5,7], which defines regenerating myofibers in transverse planes of skeletal muscle. Myonuclei are also found in a peripheral location near the sarcolemma (peripheral myonuclei) or clustered together (nuclear clusters) in regenerating myofibers [4][5][6][7][8].…”

“…The majority of myonuclei are situated in centralized linear arrays (nuclear chains) [4,5,7], which defines regenerating myofibers in transverse planes of skeletal muscle. Myonuclei are also found in a peripheral location near the sarcolemma (peripheral myonuclei) or clustered together (nuclear clusters) in regenerating myofibers [4][5][6][7][8]. The extent to which myonuclear accretion and positioning influence the maturation of regenerating myofibers is poorly understood [7].…”

“…Myonuclei are also found in a peripheral location near the sarcolemma (peripheral myonuclei) or clustered together (nuclear clusters) in regenerating myofibers [4][5][6][7][8]. The extent to which myonuclear accretion and positioning influence the maturation of regenerating myofibers is poorly understood [7].…”