Decreased SIRT1 deacetylase activity in sporadic inclusion-body myositis muscle fibers

SIRT1 belongs to the sirtuin family of NAD+-dependent histone/protein deacetylases. Experimentally, increased activity of SIRT1 facilitates calorie-restricted longevity, and decreases NF-κB activation and the amount of the amyloid-β (Aβ). We studied SIRT1 in an aging-associated muscle disease, sporadic inclusion-body myositis (s-IBM), whose muscle fibers contain increased NF-κB activation and abnormal accumulation of Aβ. We show that, as compared to the age-matched controls, in s-IBM muscle fibers: (1) SIRT1 activity and deacetylation of SIRT1 targets, H4, NF-κB and p53 were decreased; (2) SIRT1 mRNA and protein were significantly increased; (3) in the cytoplasm, SIRT1 protein was accumulated in the form of cytoplasmic aggregates; (4) in the nuclei, SIRT1 protein was decreased.To our knowledge, this is the first demonstration of SIRT1 abnormalities, including decreased SIRT1 deacetylase activity, in human disease associated with aging. We propose that in s-IBM muscle fibers, inadequate activity of SIRT1 may be detrimental by increasing NF-κB activation and contributing to abnormal Aβ accumulation. Improving SIRT1 action by treatment with known SIRT1 activators might benefit s-IBM patients.