Muscle cell communication in development and repair

Abstract

Under basal conditions, postnatal skeletal muscle displays little cell turnover. With injury, muscle initiates a rapid repair response to reseal damaged membrane, reactivating many developmental pathways to facilitate muscle regeneration and prevent tissue loss. Muscle precursor cells become activated accompanied by differentiation and fusion during both muscle growth and regeneration; inter-cellular communication is required for successful completion of these processes. Cellular communication is mediated by lipids, fusogenic membrane proteins, and exosomes. Muscle-derived exosomes carry proteins and micro RNAs as cargo. Secreted factors such as IGF-1, TGFβ, and myostatin are also released by muscle cells providing local signaling cues to modulate muscle fusion and regeneration. Proteins that regulate myoblast fusion also participate in membrane repair and regeneration. Here we will review methods of muscle cell communication focusing on proteins that mediate membrane fusion, exosomes, and autocrine factors.

Figure 1. Muscle fusion

During muscle growth and regeneration satellite cells (blue) asymmetrically divide giving rise to mono-nucleated muscle precursor cells, myoblasts (pink). Myoblasts are activated and fuse with one-another to generate nascent myotubes (orange). Myoblasts fuse with existing myotubes to promote muscle growth and regeneration (dark orange). Pax3 and Pax7 are highly expressed in satellite cells. Fusogenic proteins myoferlin, EHD2, and myomaker are highly expressed in myoblasts with expression decreasing as differentiation proceeds. Dysferlin, EHD1, and annexins have low-level expression in myoblasts with increased expression in mature muscle.

Figure 2. Exosome biogenesis and release

Exosomes are formed from multi-vescular bodies (MVBs), which are formed from endosomes. Exosomes are released as MVBs fuse with the plasma membrane. Exosome membranes are enriched with fusogenic proteins annexins (yellow), ferlins (teal), and EHDs (orange). Exosomes contain both miRNA (green) and cytosolic proteins (red) thought to participate in cell-cell communication.

Figure 3. Autocrine factors regulating muscle growth and regeneration

IGF1 is a potent muscle growth factor that binds IGF1-R activating PI3K/AKT signaling to promote protein synthesis and muscle hypertrophy. Myostatin and TGFβ are negative regulators of muscle growth inhibiting AKT induced hypertrophy through SMAD activation. miRNAs (mi-R) both regulate and are regulated by these signaling pathways adding additional layers of control to the system. mi-Rs (dark red) have been isolated from skeletal muscle derived exosomes, suggesting a mechanism by which cells can communicate and control muscle growth in a synchronous fashion. mi-Rs (pink) have been implicated in autocrine regulation but have yet to be isolated from skeletal muscle derived exosomes.