Aquaporin-4 downregulation in dysphagic patients with idiopathic inflammatory myopathies: myofiber vulnerability and inflammation drivers

Objectives To evaluate whether the impairment of aquaporin-4 (AQP4), a water channel protein important for muscle function, may be associated with dysphagia in idiopathic inflammatory myopathies (IIMs). Swallowing muscle inflammation in IIM has been documented in case reports, but direct correlations with limb muscles impairment are lacking. Methods AQP4 was immunolocalized in limb muscle biopsies. The percentage of AQP4 expressing myofibers was compared in IIM patients with and without dysphagia, and healthy controls, and correlated with muscular strength, creatine kinase level and myositis damage index. Additionally, myosin heavy chain (fast and neonatal), cluster of differentiation 68 (CD68) and matrix metalloproteinase-2 (MMP2) were immunolocalized with sarcolemma AQP4 to evaluate whether an increase in innate immunity and extracellular matrix degradation were reflected in the modified AQP4 expression. Results AQP4 immunostaining was significantly decreased in myofibers of dysphagic patients compared with normophagic patients and controls. Moreover, although both IIM groups had CD68-positive cells surrounding AQP4-negative myofibers, only in dysphagic patients AQP4-negative myofibers surrounded by CD68-positive and MMP2-positive cells were significantly increased, suggesting that inflammation from blood vessels and inflammatory cells affects AQP4 immunolocalization. Conclusion Myofiber hypotrophy appears to be due to inflammation from CD68-positive and MMP2-positive cells, whose activity disrupts the extracellular matrix and may detach AQP4 from the sarcolemma.