Dystrophin Orchestrates the Epigenetic Profile of Muscle Cells Via miRNAs

Abstract

Mammalian musculature is a very robust and dynamic tissue that goes through many rounds of degeneration and regeneration in an individual's lifetime. There is a biological program that maintains muscle progenitor cells that, when activated, give rise to intermediate myoblast progeny that consequently differentiate into mature muscle cells. Recent works have provided a picture of the role that microRNAs (miRNAs) play in maintaining aspects of this program. Intriguingly, a subset of these miRNAs is de-regulated in muscular dystrophies (MDs), a group of fatal inherited neuromuscular disorders that are often associated with deficiencies in the Dystrophin (Dys) complex. Apparently, transcriptional expression of many of the muscle specific genes and miRNAs is dependent on chromatin state regulated by the Dys-Syn-nNOS pathway. This puts Dystrophin at the epicenter of a highly regulated program of muscle gene expression in which miRNAs help to coordinate networking between multiple phases of muscle maintenance, degeneration, and regeneration. Therefore, understanding the role of miRNAs in physiology of normal and diseased muscle tissue could be useful for future applications in improving the MD therapies and could open new clinical perspectives.

Keywords: Dys–Syn–nNOS; dystrophin; epigenetic regulation; miRNAs; muscular dystrophy.

Figure 1

Muscle damage can be repaired by the progeny of satellite cells. When muscle fibers need to be replaced, signals are sent to otherwise quiescent satellite cells, which activates their proliferation and generates proliferating myoblasts. Myoblasts later differentiate and fuse to form myotubes. Myotubes cluster into myofibers, the structures that muscle cells consist of.

Figure 2

The Dys–Syn–nNOS pathway and miRNAs coordinate the muscle differentiation program. Dys–Syn–nNOS signaling regulates the epigenetic profile of muscle cells via nitrosylation of HDAC2 that influences gene expression by altering the acetylation status of histones. miR-221 and miR-222 share the same seed sequence and both target cell cycle inhibitors, p27 and p57. miR-222 also targets β1-Syn implying an impact on nNOS signaling. miR-31 temporally targets terminal differentiation genes including Dys. miR-1 and miR-133 are transcriptionally controlled by the nitrosylation state of HDAC2, which is regulated by nNOS. miR-133 targets SRF during proliferation, which in a self regulatory manner promotes expression of miR-133. miR-1 targets G6PD and HDAC4 during differentiation, and since HDAC4 regulates the transcription of muscle differentiation genes, Dys–Syn–nNOS signaling indirectly promotes differentiation. In a self-promoting regulatory loop, the expression of muscle differentiation genes results in miR-1 expression. miR-29 is also transcriptionally controlled by the nitrosylation state of HDAC2. Additional regulation of miR-29 comes from YY1, a member of NF-κB signaling. The skeletal muscle specific miRNA, miR-206 is also upregulated by muscle gene expression and aids in cell cycle inhibition by targeting DNA Pola1 and Pax7. Utrophin is another target of miR-206 providing another link between it and the DGC.

Figure 3

In dystrophic muscle the epigenetic network of muscle differentiation is disrupted. When Dys is absent, Dys–Syn–nNOS signaling is disrupted inhibiting nitrosylation of HDAC2. Consequently, levels of miR-133/miR-1 and miR-29, all of which are repressed by non-nitrosylated HDAC2, are down. The regulatory roles of miR-133/miR-1 are disturbed leading to inhibition of muscle differentiation gene expression and an increase in oxidative cellular stress. Muscle tissue generated under imbalanced conditions will contribute to the procession of adipogenesis. The decrease in miR-29 levels correlates with an increase in the amount of Collagen and Elastin that are indicative of fat and fibrotic tissue. Due to reasons that are not quite clear at this time, levels of miR-206 and miR-31 are increased altering the equilibrium between the proliferation and differentiation states. miRNAs circled in green are upregulated and miRNAs circled in red are down regulated, bold letters indicate upregulated protein levels, gray circles with diagonal lines and gray lines indicate deficiencies.

Figure 4

Myotube health regulates adipogenesis. If muscle is regenerating normally then fibro/adipogenic progenitor cells will receive a non-cell autonomous signal from the muscle environment and die. The signal from the degenerative muscle environment stimulates fibro/adipogenic progenitor cells to give rise to adipocites and fibroblasts that will differentiate into fat and fibrotic tissue.