Satellite Cells in Muscular Dystrophy - Lost in Polarity

Abstract

Recent findings employing the mdx mouse model for Duchenne muscular dystrophy (DMD) have revealed that muscle satellite stem cells play a direct role in contributing to disease etiology and progression of DMD, the most common and severe form of muscular dystrophy. Lack of dystrophin expression in DMD has critical consequences in satellite cells including an inability to establish cell polarity, abrogation of asymmetric satellite stem-cell divisions, and failure to enter the myogenic program. Thus, muscle wasting in dystrophic mice is not only caused by myofiber fragility but is exacerbated by intrinsic satellite cell dysfunction leading to impaired regeneration. Despite intense research and clinical efforts, there is still no effective cure for DMD. In this review we highlight recent research advances in DMD and discuss the current state of treatment and, importantly, how we can incorporate satellite cell-targeted therapeutic strategies to correct satellite cell dysfunction in DMD.

Keywords: Duchenne muscular dystrophy; Mark2; Par1b; Pard3; asymmetric division; dystrophin; regenerative myogenesis; satellite cells; stem cell polarity.

Figure 1. Modes of Satellite Stem Cell Division

Satellite stem cells can self-renew via symmetric or asymmetric cell divisions. A symmetric cell division along the planar axis (with respect to the myofiber) generates two stem cell daughters. Asymmetric cell divisions along the apicobasal axis give rise to a stem cell and a committed myogenic progenitor cell. Alternatively, satellite stem cells can directly express myogenic commitment factors (such as MYF5) to commit to the myogenic lineage and expand the progenitor population that will participate in muscle repair.

Figure 2. Classical Model for the Establishment of Asymmetric Stem Cell Division during Neurogenesis in Drosophila

During interphase, the Par proteins are equally distributed in the cytoplasm. The binding of Lgl to aPKC inhibits its activity. Upon activation, Aurora kinase phosphorylates Par-6 (➀) leading to the activation of aPKC (➁) which phosphorylates Lgl (➂) and forces its release (➃). Baz binds aPKC and completes the assembly of the Par complex (➄). The Par complex can now phosphorylate Par-1 (➅) and Numb (➆), leading to their relocalization to the opposite pole of the cell (➇). After activation by Polo kinase, Pon binds phosphorylated Numb (➈) and together with Par-1, act to inhibit Notch signaling (➉), thus differentially controlling fate determination in the two daughter cells.

Figure 3. Efficient Muscle Regeneration and Tissue Homeostasis Are Dependent On a Balance Between Symmetric and Asymmetric Satellite Stem Cell Divisions

Upon muscle injury within a healthy muscle, symmetric satellite cell expansion maintains the stem cell pool, while asymmetric cell divisions generate myogenic progenitors that will undergo expansion to regenerate the damaged tissue. In the context of aging, satellite stem cells favor commitment over self-renewal (increased asymmetric and reduced symmetric cell divisions) resulting in a gradual loss of stem cells. Over time, satellite stem cell decline and reduced entry into the cell cycle results in reductions of both stem and progenitor populations and an inability to efficiently perform muscle regeneration. In DMD, the loss of dystrophin-dependent polarity cues prevents satellite cells from undergoing asymmetric cell division. Shifting the balance towards symmetric stem cell division results in an increased number of satellite stem cells. An inability to perform asymmetric divisions and the associated mitotic defects may force the cells to enter a senescent state. Progressive depletion of committed progenitor cells over repetitive cycles of muscle degeneration-regeneration ultimately leads to muscle weakening.

Key Figure, Figure 4. Consequences of Cell Polarity Defects and Therapeutic Strategies to Restore Satellite Cell Function in Dystrophic Satellite Cells

A) Normal satellite stem cells undergo asymmetric division upon dystrophin-dependent polarization of MARK2 and PARD3 to opposite sides along the apicobasal axis of the dividing cell. Cell fate determinants, such as mediators of Notch signaling, are asymmetrically distributed during mitosis to enforce different cell fates (stem cell self-renewal and myogenic commitment). B) In dystrophin-deficient satellite cells, the expression of MARK2 is downregulated and PARD3 is equally distributed within the dividing cell. In the absence of polarity cues and abnormal mitotic progression, satellite stem cells undergo cell cycle arrest and may enter senescence. C) Therapeutic approaches to restore cell polarity in DMD include AAV-mediated gene delivery of dystrophin or utrophin, in vivo genome editing with CRISPR/Cas, and direct pharmacological targeting of cell polarity effectors. D) Therapeutic approaches to restore satellite cell function include treatment with WNT7a, inhibition of senescence-associated secreted factors and stimulating the autophagy pathway to prevent senescence.