Attacking Brawn and Brains: Muscle and brain cells succumb to the same protein clumps (Alzheimer's disease; Muscle)
Authors: Davenport R. John 
Published: August 2003

Geeks and jocks might not be kindred spirits in grade school, but late in life both can lose their talents to the same nemesis. Protein clumps that riddle the brain in Alzheimer's disease also crop up in muscle cells of patients with a common degenerative muscle disease called inclusion body myositis (IBM). A new mouse strain that mimics some of the cellular defects of IBM is the first to also replicate the physical symptoms. Analysis of the animals' defective tissue provides support for the idea that similar alterations in protein trimming underlie both IBM and Alzheimer's. The new tool might help scientists understand both brain and muscle degeneration.

The most common muscle disease in the elderly, IBM usually afflicts individuals over the age of 50. It causes severe muscle weakness and increases the risk for falls; it's currently untreatable. A key insight into the disease came in the early 1990s, when scientists discovered that muscle cells from IBM patients accumulate the same amyloid protein as do brain cells in Alzheimer's patients (see
"Detangling Alzheimer's Disease"
). The buildup of β amyloid seems to cause inflammation and cell death in IBM, but no one knows what triggers the disease. In the brain, plaque-forming β amyloid appears when enzymes trim the β-amyloid precursor protein (APP) in the wrong place; Sugarman and colleagues wondered whether similar mistakes in APP processing promote IBM.

To investigate that issue, the researchers engineered mice to produce large amounts of APP in muscle cells. They then measured muscle function by timing how long the rodents could balance on a rotating rod, like little lumberjacks in a log-rolling contest. Although age didn't diminish normal mice's ability to stay on the rod, older APP-producing animals fell off sooner than their younger counterparts did. In addition to decreased coordination, the altered mice displayed other symptoms of IBM. Their muscle cells showed signs of inflammation and damage and reacted with antibodies that recognize improperly clipped APP, namely, β amyloid.

Unlike previous models for IBM, the mice produce APP only in muscle cells, and their muscles are feeble. Although it's an improvement, the new model doesn't display all of IBM's hallmark signs and symptoms, cautions neurologist Valerie Askanas of the University of Southern California in Los Angeles. For example, the mouse muscle cells don't contain vacuoles, empty cellular compartments typically seen in IBM patients. But, she says, analyzing older rodents might reveal additional features of the disease. Because muscle cells are much easier to biopsy and grow in culture than brain cells are, the animals might be useful in studying the cellular changes that underlie Alzheimer's disease as well. "Thus far, much of what we know about IBM comes from studying Alzheimer's disease," says study leader Frank LaFerla of the University of California, Irvine. "Now we might have an opportunity to work backward."

--R. John Davenport

M. C. Sugarman, T. R. Yamasaki, S. Oddo, J. C. Echegoyen, M. P. Murphy, T. E. Golde, M. Jannatipour, M. A. Leissring, F. M. LaFerla, Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle.
Proc. Natl. Acad. Sci.
99
, 6334-6339 (2002).
[Abstract]
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