Peripheral nerve pathology, including aberrant Schwann cell differentiation, is ameliorated by doxycycline in a laminin- 2-deficient mouse model of congenital muscular dystrophy

Abstract

The most common form of childhood congenital muscular dystrophy, Type 1A (MDC1A), is caused by mutations in the human LAMA2 gene that encodes the laminin-α2 subunit. In addition to skeletal muscle deficits, MDC1A patients typically show a loss of peripheral nerve function. To identify the mechanisms underlying this loss of nerve function, we have examined pathology and cell differentiation in sciatic nerves and ventral roots of the laminin-α2-deficient (Lama2(-/-)) mice, which are models for MDC1A. We found that, compared with wild-type, sciatic nerves of Lama2(-/-) mice had a significant increase in both proliferating (Ki67+) cells and premyelinating (Oct6+) Schwann cells, but also had a significant decrease in both immature/non-myelinating [glial fibrillary acidic protein (GFAP)(+)] and myelinating (Krox20+) Schwann cells. To extend our previous work in which we found that doxycycline, which has multiple effects on mammalian cells, improves motor behavior and more than doubles the median life-span of Lama2(-/-) mice, we also determined how nerve pathology was affected by doxycycline treatment. We found that myelinating (Krox20+) Schwann cells were significantly increased in doxycycline-treated compared with untreated sciatic nerves. In addition, doxycycline-treated peripheral nerves had significantly less pathology as measured by assays such as amount of unmyelinated or disorganized axons. This study thus identified aberrant proliferation and differentiation of Schwann cells as key components of pathogenesis in peripheral nerves and provided proof-of-concept that pharmaceutical therapy can be of potential benefit for peripheral nerve dysfunction in MDC1A.

Congenital Muscular Dystrophies and Myopathies: An Overview and Update

“…In mice models of CMDs, drugs such as losartan and doxycycline showed beneficial effects on muscle strength and/or muscle pathology. [107][108][109] Cyclosporine A led to certain functional and histological improvement in a small Italian study of patients with Ullrich CMD. 110…”

A Family of Laminin α2 Chain-Deficient Mouse Mutants: Advancing the Research on LAMA2-CMD

“…Only recently the importance of the embryonic, pre-symptomatic stages and early pathogenesis in the different mouse models for LAMA2-CMD has been emphasized Mehuron et al, 2014;Nunes et al, 2017;Moreira Soares Oliveira et al, 2018). Likewise, associated symptoms in non-muscle tissues (peripheral and central nervous system, cardiorespiratory system) have gained attention (Hager et al, 2005;Qiao et al, 2005Qiao et al, , 2018Yang et al, 2005;Gawlik et al, 2006a, 2018, Homma et al, 2011Menezes et al, 2014;Willmann et al, 2017;Pasteuning-Vuhman et al, 2018;Rabie et al, 2019).…”

“…Peripheral neuropathy is a prominent feature of the disease also in the dy W /dy W mouse model (Kuang et al, 1998b), just like in all mouse models for LAMA2-CMD (Yurchenco et al, 2017). Several studies have explored the phenotype of peripheral nervous system in dy W /dy W mutant, showing myelination defects in sciatic nerve and ventral roots, smaller cross sectional area of sciatic nerve, as well as motor dysfunction and sensorimotor gating deficits at age of 4-6 weeks (Homma et al, 2011;Qiao et al, 2018).…”

LAMA2 Neuropathies: Human Findings and Pathomechanisms From Mouse Models

“…Apoptosis was shown to play a role in the pathology of Lama2 mice (Girgenrath et al, 2004;Dominov et al, 2005), while doxycycline, as well as other tetracycline derivatives, had been reported to inhibit apoptosis in mammalian cells (Davies et al, 2005). Thus, doxycycline was investigated in Lama2 dyW/dyW mutants where it showed amelioration of muscle and nerve pathology (Girgenrath et al, 2009;Homma et al, 2011). Although the doxycycline mechanism of action in nerves of Lama2 mutants remains vague, it might be linked to reduced cell death of immature Schwann cells and amelioration of Schwann cell differentiation (Homma et al, 2011).…”