title: Increased mitophagy in the skeletal muscle of spinal and bulbar muscular atrophy patients.
abstract: Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by polyglutamine expansion in the androgen receptor (AR) and characterized by the loss of lower motor neurons. Here we investigated pathological processes occurring in muscle biopsy specimens derived from SBMA patients and, as controls, age-matched healthy subjects and patients suffering from amyotrophic lateral sclerosis (ALS) and neurogenic atrophy. We detected atrophic fibers in the muscle of SBMA, ALS and neurogenic atrophy patients. In addition, SBMA muscle was characterized by the presence of a large number of hypertrophic fibers, with oxidative fibers having a larger size compared with glycolytic fibers. Polyglutamine-expanded AR expression was decreased in whole muscle, yet enriched in the nucleus, and localized to mitochondria. Ultrastructural analysis revealed myofibrillar disorganization and streaming in zones lacking mitochondria and degenerating mitochondria. Using molecular (mtDNA copy number), biochemical (citrate synthase and respiratory chain enzymes) and morphological (dark blue area in nicotinamide adenine dinucleotide-stained muscle cross-sections) analyses, we found a depletion of the mitochondria associated with enhanced mitophagy. Mass spectrometry analysis revealed an increase of phosphatidylethanolamines and phosphatidylserines in mitochondria isolated from SBMA muscles, as well as a 50% depletion of cardiolipin associated with decreased expression of the cardiolipin synthase gene. These observations suggest a causative link between nuclear polyglutamine-expanded AR accumulation, depletion of mitochondrial mass, increased mitophagy and altered mitochondrial membrane composition in SBMA muscle patients. Given the central role of mitochondria in cell bioenergetics, therapeutic approaches toward improving the mitochondrial network are worth considering to support SBMA patients.
authors.affiliation: Department of Neurosciences, University of Padova, Padova, Italy.
authors.forename: Doriana
authors.initials: D
authors.lastname: Borgia
authors.affiliation: Department of Neurosciences, University of Padova, Padova, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Malena
authors.affiliation: VIB Center for the Biology of Disease, KU Leuven Center for Human Genetics, Leuven, Belgium.
authors.forename: Marco
authors.initials: M
authors.lastname: Spinazzi
authors.affiliation: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy, and IRP Città della Speranza, Padova, Italy.
authors.forename: Maria Andrea
authors.initials: MA
authors.lastname: Desbats
authors.affiliation: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy, and IRP Città della Speranza, Padova, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Salviati
authors.affiliation: Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Australia.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Russell
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.|Proteomic Center of Padova University, VIMM and Padova University Hospital, Padova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Miotto
authors.affiliation: Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Tosatto
authors.affiliation: Department of Neurosciences, University of Padova, Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
authors.affiliation: Department of Neurosciences, University of Padova, Padova, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Sorarù
authors.affiliation: Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, Trento, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Pennuto
authors.affiliation: Department of Neurosciences, University of Padova, Padova, Italy.
authors.forename: Lodovica
authors.initials: L
authors.lastname: Vergani
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000503:physiopathology; D000728:Androgens / Q000378:metabolism; D000818:Animals; D001706:Biopsy; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D063306:Mitophagy / Q000235:genetics; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D020966:Muscular Disorders, Atrophic / Q000235:genetics* / Q000503:physiopathology; D010455:Peptides / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*
chemical_list: D000728:Androgens; D004272:DNA, Mitochondrial; D010455:Peptides; D011944:Receptors, Androgen; C097188:polyglutamine