Monoamine oxidase inhibition prevents mitochondrial dysfunction and apoptosis in myoblasts from patients with collagen VI myopathies

• Published in: Free radical biology & medicine 2014-10, Vol.75, p.40-47
• Main Authors: Sorato, E., Menazza, S., Zulian, A., Sabatelli, P., Gualandi, F., Merlini, L., Bonaldo, P., Canton, M., Bernardi, P., Di Lisa, F.
• Format: Article
• Language: English
• Subjects: Adult; Apoptosis - drug effects; Cell death; Cells, Cultured; Child; Child, Preschool; Collagen Type VI - genetics; Humans; Hydrogen Peroxide - pharmacology; Mitochondria; Mitochondria - pathology; Monoamine Oxidase - biosynthesis; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - pharmacology; Monoamine oxidases; Muscular Dystrophies - enzymology; Muscular dystrophy; Myoblasts - enzymology; Myoblasts - metabolism; Myoblasts - pathology; Original Contribution; Oxidative stress; Oxidative Stress - drug effects; Pargyline - pharmacology; Tyramine - pharmacology
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2014.07.006

Although mitochondrial dysfunction and oxidative stress have been proposed to play a crucial role in several types of muscular dystrophy (MD), whether a causal link between these two alterations exists remains an open question. We have documented that mitochondrial dysfunction through opening of the permeability transition pore plays a key role in myoblasts from patients as well as in mouse models of MD, and that oxidative stress caused by monoamine oxidases (MAO) is involved in myofiber damage. In the present study we have tested whether MAO-dependent oxidative stress is a causal determinant of mitochondrial dysfunction and apoptosis in myoblasts from patients affected by collagen VI myopathies. We find that upon incubation with hydrogen peroxide or the MAO substrate tyramine myoblasts from patients upregulate MAO-B expression and display a significant rise in reactive oxygen species (ROS) levels, with concomitant mitochondrial depolarization. MAO inhibition by pargyline significantly reduced both ROS accumulation and mitochondrial dysfunction, and normalized the increased incidence of apoptosis in myoblasts from patients. Thus, MAO-dependent oxidative stress is causally related to mitochondrial dysfunction and cell death in myoblasts from patients affected by collagen VI myopathies, and inhibition of MAO should be explored as a potential treatment for these diseases. Scheme of the pathway leading from Collagen VI deficiency to loss of cell viability through MAO-dependent ROS formation. The present study in human myoblasts demonstrated the role of MAO in oxidative stress and mitochondrial dysfunction confirming evidence obtained previously in mouse models of muscular dystrophy. In those models we documented also the oxidation of myofibrillar proteins that are involved in contractile impairment of viable myocites. [Display omitted] •Myoblasts of patients with collagen VI myopathies exhibit higher MAO-B expression.•Myopathic myoblasts display higher level of ROS and mitochondrial depolarization.•MAO inhibition reduces both ROS accumulation and mitochondrial dysfunction.•MAO inhibition normalizes the increased apoptosis observed in patient myoblasts.