Abstract
Oxidative stress and mitochondrial dysfunction play a crucial role in the pathophysiology of muscular dystrophies. We previously reported that the mitochondrial enzyme monoamine oxidase (MAO) is a relevant source of reactive oxygen species (ROS) not only in murine models of muscular dystrophy, in which it directly contributes to contractile impairment, but also in muscle cells from collagen VI-deficient patients. Here, we now assessed the efficacy of a novel MAO-B inhibitor, safinamide, using in vivo and in vitro models of Duchenne muscular dystrophy (DMD). Specifically, we found that administration of safinamide in 3-month-old mdx mice reduced myofiber damage and oxidative stress and improved muscle functionality. In vitro studies with myogenic cultures from mdx mice and DMD patients showed that even cultured dystrophic myoblasts were more susceptible to oxidative stress than matching cells from healthy donors. Indeed, upon exposure to the MAO substrate tyramine or to hydrogen peroxide, DMD muscle cells displayed a rise in ROS levels and a consequent mitochondrial depolarization. Remarkably, both phenotypes normalized when cultures were treated with safinamide. Given that safinamide is already in clinical use for neurological disorders, our findings could pave the way toward a promising translation into clinical trials for DMD patients as a classic case of drug repurposing.
Highlights
Duchenne muscular dystrophy (DMD) is the one of the most common and severe forms of inherited muscular dystrophies
Even though safinamide did not lead to significant improvements in normalized force (Figure 1A), treated animals showed a strong and significant reduction in force drop upon eccentric contractions, a typical hallmark of dystrophic muscles (Figure 1B)
Both safinamide regimens induced a significant improvement in the resistance against eccentric contractions (Figure 2A), while no significant improvement in normalized force could be found in safinamide-treated mdx mice compared to controls (Figure 2B)
Summary
Duchenne muscular dystrophy (DMD) is the one of the most common and severe forms of inherited muscular dystrophies. We have already reported that MAO expression and activity increase in muscles from two murine models of muscular dystrophies, mdx for DMD and Col6a1−/− mice for collagen VI-related myopathies (Menazza et al, 2010) This results in excessive levels of H2O2, which in turn alters the redox homeostasis and causes myofibrillar protein oxidation, hampering contractile function. The involvement of MAO in muscular dystrophy has been seen in in vitro myoblasts cultures obtained from patients with collagen VI myopathies (Sorato et al, 2014) In these cells, pargyline treatment reduced ROS accumulation and mitochondrial dysfunction, while normalizing the occurrence of apoptosis. These findings proved that MAO-dependent ROS accumulation is directly linked to mitochondrial dysfunction and suggested that it is upstream of the opening of the permeability transition pore (Sorato et al, 2014)
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