Mitochondrial profile and amyloidogenic molecules in sporadic inclusion body myositis

Sporadic inclusion body myositis (sIBM) is the most common myopathy in elderly. This disease causes muscle wasting with both distal and proximal affectation. Quadriceps and finger flexors are muscle typically affected. At pathological level, three different features are present in muscle biopsies: inflammation, mitochondrial abnormalities and degeneration. The presence of T-cell infiltrate, ragged-red fibers and rimmed vacuoles are some features linked to these pathological processes. Protein misfolding and aggregation lead to the formation of the mentioned rimmed vacuoles, composed by many different misfolded proteins: β-amyloid, caveolin, phosphor-Tau among others. The accumulation of β-amyloid is also a hallmark of Alzheimer’s disease (AD), which presents some parallelisms with sIBM.\n\n\t\t\t\t In this work, we aimed to evaluate the mitochondrial state in muscle from sIBM patients but also in peripheral blood mononuclear cells (PBMC) to describe the molecular abnormalities that mitochondria could present in this disease. In addition, we aimed to measure plasmatic molecules related to inflammation, mitochondria and degeneration, in search for plasmatic biomarkers in sIBM patients but also in dermatomyositis and polymyositis, both diseases from the inflammatory myopathy group, like sIBM.\n\n\t\t\t\t Regarding mitochondrial analysis, muscle biopsies from 23 sIBM patients were analyzed, as well as 18 controls free of muscle disease. In addition, PBMC from 14 sIBM patients and from 20 controls were assessed as well. MtDNA levels and also mitochondrial respiratory chain complex IV (COX) activity were significantly decreased in muscle from sIBM patients compared to controls. Interestingly, when analyzing PBMC, dysfunction in COX activity was also found. In this tissue, a deregulation in mitochondrial protein synthesis was also found. As 57% of the sIBM patients presented mtDNA deletions, we aimed to evaluate if the presence of mtDNA deletions correlate with impaired mitochondrial parameters. sIBM patients with mtDNA deletions presented the lowest amount of mtDNA, and those patients without deletions showed values more similar to controls. A similar pattern was found when correlating the presence of MFN-2, a protein involved in mitochondrial dynamics. Again, patients with mtDNA deletions presented the lowest amount of this protein, and patients without deletions showed an intermediate values between patients with deletions and controls.\n\n\t\t\t\t Regarding the analysis of plasmatic molecules related to sIBM pathological features, inflammatory, mitochondrial and amyloidogenic molecules were analyzed in plasma samples from 21 sIBM, 20 controls and also in 14 plasma samples from dermatomyositis (DM) and polymyositis (PM) patients, which constitute an inflammatory myopathy different from sIBM group. Inflammatory (IL-6 and TNF-α) and mitochondrial-related (circulating mtDNA, FGF-21 and CoQ) molecules did not show significant differences between groups. However, amyloidogenic molecules (BACE-1, PS-1 and sAPPβ) were increased in sIBM patients respect to controls but also respect to the DM and PM group confirming its implication in sIBM pathogenesis. Sensitivity and specificity test showed that BACE-1 would be the most suitable biomarker for sIBM diagnosis.\n\n\t\t\t\t This thesis describes at molecular level the mitochondrial implication in the disease, and also reinforces the amyloidogenic component in sIBM. In addition, it proposes a plasmatic and non-invasive biomarker that could help in the sIBM diagnosis, especially in discriminating between other inflammatory myopathies, like polymyositis.