Oxidative stress by monoamine oxidases is causally involved in myofiber damage in muscular dystrophy.
Several studies documented the key role of oxidative stress and abnormal production of reactive oxygen species (ROS) in the pathophysiology of muscular dystrophies (MDs). The sources of ROS, however, are still controversial as well as their major molecular targets. This study investigated whether ROS produced in mitochondria by monoamine oxidase (MAO) contributes to MD pathogenesis. Pargyline, an MAO inhibitor, reduced ROS accumulation along with a beneficial effect on the dystrophic phenotype of Col6a1(-/-) mice, a model of Bethlem myopathy and Ullrich congenital MD, and mdx mice, a model of Duchenne MD. Based on our previous observations on oxidative damage of myofibrillar proteins in heart failure, we hypothesized that MAO-dependent ROS might impair contractile function in dystrophic muscles. Indeed, oxidation of myofibrillar proteins, as probed by formation of disulphide cross-bridges in tropomyosin, was detected in both Col6a1(-/-) and mdx muscles. Notably, pargyline significantly reduced myofiber apoptosis and ameliorated muscle strength in Col6a1(-/-) mice. This study demonstrates a novel and determinant role of MAO in MDs, adding evidence of the pivotal role of mitochondria and suggesting a therapeutic potential for MAO inhibition.
Menazza
Sara
S
Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy.
Blaauw
Bert
B
Tiepolo
Tania
T
Toniolo
Luana
L
Braghetta
Paola
P
Spolaore
Barbara
B
Reggiani
Carlo
C
Di Lisa
Fabio
F
Bonaldo
Paolo
P
Canton
Marcella
M
D000818:Animals; D024142:Collagen Type VI / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000378:metabolism*; D009137:Muscular Dystrophy, Animal / Q000473:pathology*; D009210:Myofibrils / Q000473:pathology*; D018384:Oxidative Stress; D010641:Phenotype
C540085:Col6a1 protein, mouse; D024142:Collagen Type VI; D008995:Monoamine Oxidase