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Arthritis Rheum. 2012 Nov;64(11):3750-9. doi: 10.1002/art.34625.

The molecular basis of skeletal muscle weakness in a mouse model of inflammatory myopathy.

Author information

  • 1Children's National Medical Center, Washington, DC, USA.

Abstract

OBJECTIVE:

It is generally believed that muscle weakness in patients with polymyositis and dermatomyositis is due to autoimmune and inflammatory processes. However, it has been observed that there is a poor correlation between the suppression of inflammation and a recovery of muscle function in these patients. This study was undertaken to examine whether nonimmune mechanisms also contribute to muscle weakness. In particular, it has been suggested that an acquired deficiency of AMP deaminase 1 (AMPD1) may be responsible for muscle weakness in myositis.

METHODS:

We performed comprehensive functional, behavioral, histologic, molecular, enzymatic, and metabolic assessments before and after the onset of inflammation in a class I major histocompatibility complex (MHC)-transgenic mouse model of autoimmune inflammatory myositis.

RESULTS:

Muscle weakness and metabolic disturbances were detectable in the mice prior to the appearance of infiltrating mononuclear cells. Force contraction analysis of muscle function revealed that weakness was correlated with AMPD1 expression and was myositis specific. Decreasing AMPD1 expression resulted in decreased muscle strength in healthy mice. Fiber typing suggested that fast-twitch muscles were converted to slow-twitch muscles as myositis progressed, and microarray results indicated that AMPD1 and other purine nucleotide pathway genes were suppressed, along with genes essential to glycolysis.

CONCLUSION:

These data suggest that an AMPD1 deficiency is acquired prior to overt muscle inflammation and is responsible, at least in part, for the muscle weakness that occurs in the mouse model of myositis. AMPD1 is therefore a potential therapeutic target in myositis.

Copyright © 2012 by the American College of Rheumatology.

PMID:
22806328
[PubMed - indexed for MEDLINE]
PMCID:
PMC3485437
Free PMC Article

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