title: Mitochondrial dysfunction in skeletal muscle of amyloid precursor protein-overexpressing mice.
abstract: Inclusion body myositis, the most common muscle disorder in the elderly, is partly characterized by abnormal expression of amyloid precursor protein (APP) and intracellular accumulation of its proteolytic fragments collectively known as β-amyloid. The present study examined the effects of β-amyloid accumulation on mitochondrial structure and function of skeletal muscle from transgenic mice (MCK-βAPP) engineered to accumulate intramyofiber β-amyloid. Electron microscopic analysis revealed that a large fraction of myofibers from 2-3-month-old MCK-βAPP mice contained numerous, heterogeneous alterations in mitochondria, and other cellular organelles. [(1)H-decoupled](13)C NMR spectroscopy showed a substantial reduction in TCA cycle activity and indicated a switch from aerobic to anaerobic glucose metabolism in the MCK-βAPP muscle. Isolated muscle fibers from the MCK-βAPP mice also exhibited a reduction in cytoplasmic pH, an increased rate of ROS production, and a partially depolarized plasmalemma. Treatment of MCK-βAPP muscle cells with Ru360, a mitochondrial Ca(2+) uniporter antagonist, reversed alterations in the plasmalemmal membrane potential (V(m)) and pH. Consistent with altered redox state of the cells, treatment of MCK-βAPP muscle cells with glutathione reversed the effects of β-amyloid accumulation on Ca(2+) transient amplitudes. We conclude that structural and functional alterations in mitochondria precede the reported appearance of histopathological and clinical features in the MCK-βAPP mice and may represent key early events in the pathogenesis of inclusion body myositis.
authors.affiliation: CeSI-Centro Scienze dell'Invecchiamento and DNI-Department of Neuroscience and Imaging, University Gabriele d'Annunzio, I-66100 Chieti, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Boncompagni
authors.forename: Charbel E-H
authors.initials: CE
authors.lastname: Moussa
authors.forename: Ezra
authors.initials: E
authors.lastname: Levy
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Pezone
authors.forename: José R
authors.initials: JR
authors.lastname: Lopez
authors.forename: Feliciano
authors.initials: F
authors.lastname: Protasi
authors.forename: Alexander
authors.initials: A
authors.lastname: Shtifman
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002952:Citric Acid Cycle / Q000235:genetics; D003593:Cytoplasm; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D018979:Myositis, Inclusion Body / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction
chemical_list: D016564:Amyloid beta-Protein Precursor; D005947:Glucose; D002118:Calcium