title: Subcellular effects of myocyte-specific androgen receptor overexpression in mice.
abstract: Although androgen receptor (AR) within myocytes is thought to mediate many of the effects of testosterone and other androgens on skeletal muscle, little is known about the functions of AR within these cells. We, therefore, studied the ultrastructure of skeletal muscle of HSA-AR transgenic (Tg) mice that overexpress AR selectively in myocytes and exhibit neuromuscular atrophy. We examined male HSA-AR mice from two different founding lines: L78 (lower copy number and less severe phenotype) and L141 (higher copy number and more severe phenotype) and compared these to wild-type (Wt) brothers. We also examined testosterone-treated female mice from these two lines and compared them both to their Wt sisters and to vehicle-treated controls. Ultrastructural examination of extensor digitorum longus sections using transmission electron microscopy revealed remarkably disorganized myofibrils in male Tg and testosterone-treated female Tg mice. Quantification of ultrastructural pathology indicated reduced myofibril width, hypertrophic and hyperplastic intermyofibrillar mitochondria, and pronounced glycogen accumulation in HSA-AR males of both lines. Reduced myofibrillar width and increases in mitochondrial number, size, and volume density were also observed in testosterone-treated HSA-AR females, although glycogen accumulation was not observed. Structural abnormalities in mitochondria were also associated with increases in electron transport chain activity and systemic resting metabolic rate, indicative of hypermetabolism. We find that overexpression of AR in myocytes of HSA-AR mice results in alterations in myofibrils, mitochondria, and glycogen. Alterations in myofibrils and mitochondria appear to result from acute actions of testosterone, whereas those on glycogen do not. Pathology of myofibrils and/or mitochondria may, therefore, mediate in part the neuromuscular atrophy observed in HSA-AR mice.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 3G3.
authors.forename: Mutaz
authors.initials: M
authors.lastname: Musa
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Fernando
authors.forename: Diptendu
authors.initials: D
authors.lastname: Chatterjee
authors.forename: D Ashley
authors.initials: DA
authors.lastname: Monks
mesh_terms: D000818:Animals; D001284:Atrophy; D001481:Basal Metabolism; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D006003:Glycogen / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009210:Myofibrils / Q000187:drug effects / Q000473:pathology; D009468:Neuromuscular Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics; D012737:Sex Factors; D013739:Testosterone / Q000633:toxicity
chemical_list: D045222:Electron Transport Chain Complex Proteins; D009124:Muscle Proteins; D011944:Receptors, Androgen; D013739:Testosterone; D006003:Glycogen