Mitochondrial dysfunction in skeletal muscle of amyloid precursor protein-overexpressing mice

Simona Boncompagni, Charbel E H Moussa, Ezra Levy, Matthew J. Pezone, José R. Lopez, Feliciano Protasi, Alexander Shtifman

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22 Scopus citations


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. [ 1H-decoupled]13C 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 Ca2+ 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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)20534-20544
Number of pages11
JournalJournal of Biological Chemistry
Issue number24
StatePublished - Jun 8 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Medicine(all)
  • Molecular Biology
  • Cell Biology


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