| First Author | Boncompagni S | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 24 | Pages | 20534-44 |
| PubMed ID | 22518836 | Mgi Jnum | J:186515 |
| Mgi Id | MGI:5432460 | Doi | 10.1074/jbc.M112.359588 |
| Citation | Boncompagni S, et al. (2012) Mitochondrial dysfunction in skeletal muscle of amyloid precursor protein-overexpressing mice. J Biol Chem 287(24):20534-44 |
| abstractText | 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 beta-amyloid. The present study examined the effects of beta-amyloid accumulation on mitochondrial structure and function of skeletal muscle from transgenic mice (MCK-betaAPP) engineered to accumulate intramyofiber beta-amyloid. Electron microscopic analysis revealed that a large fraction of myofibers from 2-3-month-old MCK-betaAPP 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-betaAPP muscle. Isolated muscle fibers from the MCK-betaAPP mice also exhibited a reduction in cytoplasmic pH, an increased rate of ROS production, and a partially depolarized plasmalemma. Treatment of MCK-betaAPP 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-betaAPP muscle cells with glutathione reversed the effects of beta-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-betaAPP mice and may represent key early events in the pathogenesis of inclusion body myositis. |
