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

Abstract

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.

Novel pathogenic variants and genes for myopathies identified by whole exome sequencing

“…2014; Sorato et al. 2014). While muscle biopsy histology and EM did not reveal defects in morphology or number of mitochondria, respiratory chain deficits may explain the weight loss and fatigue seen in these patients.…”

“…Case 2 suffered from intermittent sleeping problems, but a sleep study did not reveal any apnea. Alternatively, several papers demonstrate metabolic changes in UCMD and BM including mitochondrial deficits in mouse models, cell models from UCHM and BM patients, and in patient muscle biopsies (Tagliavini et al 2013;De Palma et al 2014;Sorato et al 2014). While muscle biopsy histology and EM did not reveal defects in morphology or number of mitochondria, respiratory chain deficits may explain the weight loss and fatigue seen in these patients.…”

Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases

“…Other documented sources of ROS in mitochondria include monoamine oxidase and dihydroorotate dehydrogenase (Cadenas , Davies, 2000;Lenaz, 2001). The former enzyme was previously demonstrated to be involved in oxidative damage in myocytes from patients with collagen V myopathies (Sorato et al, 2014). In addition, the flavoproteins acyl-CoA dehydrogenase and glycerol phosphate dehydrogenase can produce ROS in tissues during the oxidation of lipid-derived substrates (Lambertucci et al, 2008;St-Pierre et al, 2002).…”

The Mitochondrial Permeability Transition Pore: Channel Formation by F-ATP Synthase, Integration in Signal Transduction, and Role in Pathophysiology

“…Collagen VI deficiency impairs anchoring of skeletal muscle fibers to the matrix, exposing muscles to extensive mechanical stress that eventually leads to death of muscle fibers (341). We have shown that PTP induction is the effector mechanism responsible for the loss of muscle fibers in collagen VI null mice (287) in a process that involves ROS production by mitochondrial monoamine oxidases (539). Mitochondrial dysfunction and cell death could be prevented both in mice and in myoblasts from Ullrich patients by treatment with CsA and other CyPD inhibitors devoid of immunosuppressive activity, paving the way to the use of PTP inhibitors for the treatment of patients (43, 407,669).…”