Intracellular deposition of the -amyloid (A) peptide is an increasingly recognized pathological hallmark associated with neurodegeneration and muscle wasting in Alzheimer’s disease (AD) and inclusion body myositis (IBM), respectively. Previous reports have implicated dysregulation of -amyloid precursor protein (APP) expression in IBM. Accumulation of full-length APP, its various proteolytic derivatives including A, and phospho-tau into vacuolated inclusions is an early pathogenic event. We previously reported on a statistical tendency favoring fast twitch fiber involvement in IBM, reminiscent of the tissue specific patterns of misfolded protein deposition seen in neurodegenerative diseases. To test this principle, we generated an animal model in which human wild-type (WT) APP expression was limited to postnatal type II skeletal muscle. Hemizygous transgenic mice harboring increased levels of holoAPP751 and A in skeletal muscle fibers became significantly weaker with age compared with nontransgenic littermates and exhibited typical myopathic features. A subpopulation of dissociated muscle fibers from transgenic mice exhibited a 2-fold increase in resting calcium and membrane depolarization compared with nontransgenic littermates. Taken together, these data indicate that overexpression of human APP in fast twitch skeletal muscle of transgenic mice is sufficient for the development of some features characteristic of IBM, including abnormal tau histochemistry. The increase in resting calcium and depolarization are novel findings, suggesting both a mechanism for the weakness and an avenue for therapeutic intervention in IBM.--Moussa, C. E-H., Fu, Q., Kumar, P., Shtifman, A., Lopez, J. R., Allen, P. D., LaFerla, F., Weinberg, D., Magrane, J., Aprahamian, T., Walsh, K., Rosen, K. M., Querfurth, H. W. Transgenic expression of -APP in fast-twitch skeletal muscle leads to calcium dyshomeostasis and IBM-like pathology.