Skeletal muscle inflammation of unknown cause is referred to as idiopathic inflammatory myopathy, or myositis. Muscle weakness is one of the characteristic features of such disease conditions. It is known that in some patients, there is litle direct relationship between skeletal muscle inflammation and the degree of weakness and disability. One of the paradoxes of myositis is that the inflammation can be cured, but the patient's weakness cannot. We have hypothesized that muscle weakness is independent of inflammation but is dependent on a metabolic enzyme, AMP deaminase 1 (AMPD1). AMPD1 is a purine nucleotide cycle enzyme that is activated in skeletal muscle during short-term, high-intensity exercise when the rate of ATP utilization exceeds the potential of the cells to resynthesize ATP. We propose that the relatively poor correlation between inflammation and weakness in myositis is due to the secretion of innate immune cytokines that down-regulate AMPD1 expression, interfere with energy production, and cause the weakness and fatigue of myositis. Here we will pursue this hypothesis through the following aims.
Aim 1 : Determine whether reduced AMPD1 expression causes weakness in wild-type mice and worsens weakness in myositis mice.
Aim 2 : Identify innate cytokine-induced transcription factors by promoter analysis in muscle cell cultures.
Aim 3 : Determine whether modulating cytokine signaling improves muscle function in myositis mice. These studies will elucidate the mechanisms of muscle weakness and dysfunction and provide clues to identify therapeutic targets for correcting weakness in these patients.
Although the group of muscle inflammation diseases known as myositis is treated with drugs to diminish inflammation and the immune system, the myositis-associated muscle weakness often persists after the inflammation is cured. The proposed study will use cell cultures and mice to investigate how certain immune system molecules (cytokines) regulate an enzyme involved in muscle metabolism (AMPD1) and how that enzyme influences muscle weakness in myositis. These studies will help us to understand why muscle weakness occurs in myositis, and thus provide improved therapeutic strategies for those who suffer from persistent myositis.