TRIM63 and Atrogin-1 are key drivers of systemic and muscle inflammation in patients with idiopathic inflammatory myopathies.

Abstract

Objectives: The ubiquitin proteasome system is the main mediator of inflammation-induced muscle atrophy through the expression of TRIM63 and Atrogin-1. The aim of this study was to address the expression of these ubiquitin ligases and their relationship with inflammatory and atrophy parameters of patients with idiopathic inflammatory myopathies (IIM).

Methods: We recruited 37 adult IIM patients, and 10 age and sex-matched healthy donors. We assessed the proportion of different peripheral blood mononuclear cells (PBMC) subsets expressing TRIM63 and Atrogin-1 and the serum amount of theses ubiquitin ligases, cytokines, and chemokines, using multiparametric flow-cytometry, ELISA and luminometry respectively. The muscle expression of TRIM63 and Atrogin-1 was assessed by confocal microscopy. We compared the quantitative variables with the Mann-Whitney U test and assessed the correlations with Spearman Rho.

Results: IIM patients had a higher proportion of TRIM63+ CD4+ T cells (24.56 (7.71-53.23) vs. 2.55 (0.42-4.51), p<0.0001), TRIM63+ CD8+ T cells (15.1 (3.22-37.40) vs. 1.06 (0.83-2.45), p=0.0002), TRIM63+ monocytes (14.09 (3.25-29.80) vs. 1.97 (0.59-7.64), p=0.011), Atrogin-1+ CD4+ T cells (27.30 (6.61-64.19) vs. 2.55 (0.42-4.51), p<0.0001), Atrogin-1+ CD8+ T cells (14.88 (5.99-34.30) vs. 2.33 (0.60-8.01), p=0.001), and Atrogin1+ monocytes (17.38 (8.93-47.37) vs. 1.41 (0.79-3.77), p<0.0001). Muscle from IIM patients had a higher expression of TRIM63 and Atrogin-1. TRIM63+ CD8+ T cells mainly correlated with serum IL-2, IL-4, IL-8, IL-10, G-CSF, and TNF-a.

Conclusions: TRIM63 and Atrogin-1 are expressed in PBMC and muscle from patients with IIM and correlate with serum cytokines, and chemokines. This mechanism may contribute to the inflammation-induced muscle atrophy in IIM.