Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle

Michael C. Sugarman, Tritia R. Yamasaki, Salvatore Oddo, Julio C. Echegoyen, M. Paul Murphy, Todd E. Golde, Mehrdad Jannatipour, Malcolm A. Leissring, Frank M. LaFerla

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobio-chemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-β peptide, which is derived from proteolysis of the larger amyloid-β precursor protein (βAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of βAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted βAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to βAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of βAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for βAPP mismetabolism in human IBM.

Original languageEnglish (US)
Pages (from-to)6334-6339
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number9
DOIs
StatePublished - Apr 30 2002
Externally publishedYes

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Inclusion Body Myositis
Amyloid beta-Protein Precursor
Skeletal Muscle
Phenotype
Transgenic Mice
Alzheimer Disease
MM Form Creatine Kinase
Muscles
Brain Diseases
Human Body
Amyloid
Neurodegenerative Diseases
Proteolysis
Inflammation
Peptides
Population

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle. / Sugarman, Michael C.; Yamasaki, Tritia R.; Oddo, Salvatore; Echegoyen, Julio C.; Murphy, M. Paul; Golde, Todd E.; Jannatipour, Mehrdad; Leissring, Malcolm A.; LaFerla, Frank M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 9, 30.04.2002, p. 6334-6339.

Research output: Contribution to journalArticle

Sugarman, MC, Yamasaki, TR, Oddo, S, Echegoyen, JC, Murphy, MP, Golde, TE, Jannatipour, M, Leissring, MA & LaFerla, FM 2002, 'Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle', Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 9, pp. 6334-6339. https://doi.org/10.1073/pnas.082545599
Sugarman, Michael C. ; Yamasaki, Tritia R. ; Oddo, Salvatore ; Echegoyen, Julio C. ; Murphy, M. Paul ; Golde, Todd E. ; Jannatipour, Mehrdad ; Leissring, Malcolm A. ; LaFerla, Frank M. / Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle. In: Proceedings of the National Academy of Sciences of the United States of America. 2002 ; Vol. 99, No. 9. pp. 6334-6339.
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