Detection of elevated Nε-carboxymethyllysine levels in muscular tissue and in serum of patients with fibromyalgia

Objectives: To compare levels of the advanced glycation end product ( AGE) N-epsilon-carboxymethyllysine (CML) present in the muscle tissue and in the serum of patients with fibromyalgia ( FM) vs. healthy controls. Methods: The serum levels of CML were measured in 41 patients with FM and 81 healthy controls. The presence of CML, nuclear factor kappa B (NF-kappa B), the AGE receptor (RAGE), collagen types I, II, VI, and CD68-positive monocytes/macrophages in muscle tissue of 14 patients with FM was investigated by immunohistochemistry. Results: Patients with FM showed significantly increased serum levels of CML in comparison to healthy controls. The immunohistochemical investigation revealed a stronger staining for CML and NF-kappa B and more CD68-positive monocytes/macrophages in the muscle of FM patients. The collagens and CML were colocalized, suggesting that the AGE modifications were related to collagen. RAGE was absent in controls but a faint and patchy staining was seen in FM. Conclusions: In the interstitial connective tissue of fibromyalgic muscles we found a more intensive staining of the AGE CML, activated NF-kappa B, and also higher CML levels in the serum of these patients compared to the controls. RAGE was only present in FM muscle. AGE modification of proteins causes reduced solubility and high resistance to proteolytic digestion of the altered proteins ( e. g. AGE-modified collagens). AGEs can stimulate different types of cells by activation of the transcription factor NF-kappa B, mediated by specific receptors of AGEs ( e. g. RAGE) on the cell surface. Both mechanisms may contribute to the development, perpetuation, and spreading of pain characteristic in FM patients.