Myogenic Cell Expression of Intercellular Adhesion Molecule-1 Contributes to Muscle Regeneration after Injury

Abstract

This study investigated intercellular adhesion molecule-1 (ICAM-1), a membrane protein that mediates cell-to-cell adhesion and communication, as a mechanism through which the inflammatory response facilitates muscle regeneration after injury. Toxin-induced muscle injury to tibialis anterior muscles of wild-type mice caused ICAM-1 to be expressed by a population of satellite cells/myoblasts and myofibers. Myogenic cell expression of ICAM-1 contributed to the restoration of muscle structure after injury, as regenerating myofibers were more abundant and myofiber size was larger for wild-type compared with Icam1 À/À mice during 28 days of recovery. Contrastingly, restoration of muscle function after injury was similar between the genotypes. ICAM-1 facilitated the restoration of muscle structure after injury through mechanisms involving the regulation of myofiber branching, protein synthesis, and the organization of nuclei within myofibers after myogenic cell fusion. These findings provide support for a paradigm in which ICAM-1 expressed by myogenic cells after muscle injury augments their adhesive and fusogenic properties, which, in turn, facilitates regenerative and hypertrophic processes that restore structure to injured muscle.

Positional Context of Myonuclear Transcription during Injury-induced Muscle Regeneration

“…The observed kinetics in myonuclear accretion is consistent with the robust myogenic cell proliferation and fusion that normally occurs within 7 days of an injury (Millay et al, 2014;Dumont et al, 2015;Hardy et al, 2016;Webster et al, 2016;Bi et al, 2018). Why regenerating myofibers contain a greater number of myonuclei (myonuclei/100μm) than control myofibers is unknown (Martin et al, 2020) (present study). We suspect that the elevated number of myonuclei in regenerating myofibers reflects the pro-fusion environment of injured muscle, as opposed to the involvement of an unknown mechanism that dictates myonuclear number during an early stage of regeneration.…”

“…To substantiate and extend our prior work (Martin et al, 2020), we quantified myonuclear number before and during regeneration (Figure 1A). The number of myonuclei in regenerating myofibers (myonuclei/100 μm) was 63-73% higher at 7, 14, and 28 days post-injury compared to control (0 days post-injury) levels (Figure 1B).…”

“…The decrease in myonuclear density during the course of regeneration likely reflects the expansion of myofiber volume, as opposed to the loss of myonuclei. This interpretation is based on the finding that myofibers were undergoing hypertrophy during regeneration (Figure 1C) while myonuclear number (myonuclei/100μm) remains relatively constant (Figure 1B) (Martin et al, 2020). Furthermore, we are not aware of any evidence of myonuclear apoptosis or autophagy during regeneration.…”

“…In contrast to our detailed understanding of transcription in proliferating and differentiating myogenic cells (Parker et al, 2003; Braun and Gautel, 2011), the identity and spatial distribution of regulators of transcription (e.g., transcription factors) in regenerating myofibers remains to be determined. Myonuclei in nuclear chains are very closely aligned in a central location between myofibrils within regenerating myofibers (Newlands et al, 1998; Wada et al, 2008; Martin et al, 2020); whereas those in a peripheral position are separated from each other and near the sarcolemma (Bruusgaard et al, 2003; Bruusgaard et al, 2006). These anatomical differences could explain the positional context of transcription if regulators of transcription tend to localize near nuclear chains and/or if there is an exchange of nuclear content between neighboring myonuclei within nuclear chains.…”

Positional Context of Myonuclear Transcription During Injury-Induced Muscle Regeneration

“…These processes are referred to as muscle regeneration and commence with the proliferation of muscle stem cells called satellite cells ( Relaix and Zammit, 2012 ; Dumont et al, 2015 ). Sustained fusion of progenitor cells derived from satellite cells results in the accumulation of hundreds of nuclei (myonuclei) within newly formed (regenerating) myofibers ( Krauss, 2010 ; Pavlath, 2011 ; Millay et al, 2014 ; Bi et al, 2018 ; Martin et al, 2020 ). Myonuclear accretion increases the capacity of regenerating myofibers to transcribe genes; which in theory optimizes their maturation through mechanisms that govern transcription and translation.…”