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Serum exosomes can restore cellular function in vitro and be used for diagnosis in dysferlinopathy.

ABSTRACT: Purpose: It is challenging to deliver the full-length dysferlin gene or protein to restore cellular functions of dysferlin-deficient (DYSF^-/-) myofibres in dysferlinopathy, a disease caused by the absence of dysferlin, which is currently without effective treatment. Exosomes, efficient membranous nanoscale carriers of biological cargoes, could be useful. Experimental design: Myotube- and human serum-derived exosomes were investigated for their capabilities of restoring dysferlin protein and cellular functions in murine and human DYSF^-/- cells. Moreover, dysferlinopathic patient serum- and urine-derived exosomes were assessed for their abilities as diagnostic tools for dysferlinopathy. Results: Here we show that exosomes from dysferlin-expressing myotubes carry abundant dysferlin and enable transfer of full-length dysferlin protein to DYSF^-/- myotubes. Exogenous dysferlin correctly localizes on DYSF^-/- myotube membranes, enabling membrane resealing in response to injury. Human serum exosomes also carry dysferlin protein and improve membrane repair capabilities of human DYSF^-/- myotubes irrespective of mutations. Lack of dysferlin in dysferlinopathic patient serum and urine exosomes enables differentiation between healthy controls and dysferlinopathic patients. Conclusions: Our findings provide evidence that exosomes are efficient carriers of dysferlin and can be employed for the treatment and non-invasive diagnosis of dysferlinopathy.

SUBMITTER: Dong X

PROVIDER: S-EPMC5835933 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSilent Information Regulator 2 (SIRT2) protein inhibition has been shown to play a neuroprotective role in acute ischemic stroke (AIS) in mice. However, its role in AIS patients has not been fully understood. In this study, we aimed to analyze SIRT2 protein expression in serum exosomes of AIS and non-AIS patients, and evaluate its potential role in diagnosis and prognosis of AIS.MethodsSerum exosomes from 75 non-AIS subjects and 75 AIS patients were isolated. The SIRT2 protein levels in exosomes were analyzed using enzyme linked immunosorbent assay (ELISA). The National Institutes of Health Stroke Scale (NIHSS) was used to evaluate the severity of the disease. The modified Rankin Scale (mRS) was employed to assess the functional outcomes of the patients at 3-months following stroke onset.ResultsThe SIRT2 protein concentration of serum exosomes were higher in AIS patients than non-AIS patients (p < 0.001). Furthermore, the receiver operative characteristic curve (ROC) demonstrated that higher serum exosome SIRT2 could differentiate AIS patients from non-AIS patients with a sensitivity of 81.3% and a specificity of 75.3%. The area under the curve was 0.838 (95% CI: 0.775, 0.902). Additionally, higher SIRT2 concentration of serum exosomes were associated with NIHSS ≥ 4 (p < 0.001) and mRS ≥ 3 (p = 0.025) in AIS patients. The ROC analysis showed SIRT2 could discriminate stroke with NIHSS ≥ 4 from mild stroke (NIHSS < 4) with a sensitivity of 75.0% and a specificity of 69.6%. The area under the curve was 0.771 (95% CI: 0.661,0.881). Similarly, the test showed SIRT2 could differentiate between AIS patients with mRS ≥ 3 from those with mRS < 3 with a sensitivity of 78.3% and a specificity of 51.9%. The area under the curve was 0.663 (95% CI: 0.531,0.796). The logistic regression analysis revealed that SIRT2 concentration in serum exosomes can independently predict the diagnosis of AIS (odd ratio = 1.394, 95%CI 1.231-1.577, p < 0.001) and higher NIHSS scores (≥ 4) (odd ratio = 1.258, 95%CI 1.084-1.460, p = 0.002). However, it could not independently predict the prognosis of AIS (odd ratio = 1.065, 95%CI 0.983-1.154, p = 0.125).ConclusionThe elevation of SIRT2 in serum exosomes may be a valuable biomarker of AIS, which may be a potential diagnostic tool to facilitate decision making for AIS patients.

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Serum exosomes can restore cellular function in vitro and be used for diagnosis in dysferlinopathy.

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