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 patients. We have therefore hypothesized that non-immune mechanisms also contribute to muscle weakness. In particular, it has been suggested that an acquired deficiency of AMP deaminase (AMPD1) may be responsible for muscle weakness in myositis.
We have used comprehensive functional, behavioral, histological, molecular, enzymatic and metabolic assessments before and after the onset of inflammation in MHC class I mouse model of autoimmune inflammatory myositis.
We found that 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 AMDP1 expression and was myositis-specific. We also demonstrated that decreasing AMPD1 expression results in decreased muscle strength in healthy mice. Fiber typing suggested that fast-twitch muscles are converted to slow-twitch muscles as myositis progresses, and microarray results indicated that AMPD1 and other purine nucleotide pathway genes are suppressed, along with genes essential to glycolysis.
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.