Inhibiting the inflammasome with MCC950 counteracts muscle pyroptosis and improves Duchenne muscular dystrophy

Background: Duchenne muscular dystrophy (DMD) is the most common inherited human myopathy. Typically, the secondary process involving severe inflammation and necrosis exacerbate disease progression. Previously, we reported that the NLRP3 inflammasome complex plays a crucial role in this disorder. Moreover, pyroptosis, a form of programmed necrotic cell death, is triggered by NLRP3 via gasdermin D (GSDMD). So far, pyroptosis has never been described either in healthy muscle or in dystrophic muscle. The aim of this study was to unravel the role of NLRP3 inflammasome in DMD and explore a potentially promising treatment with MCC950 that selectively inhibits NLRP3. Methods: Four‐week‐old mdx mice (n=6 per group) were orally treated for 2 months with MCC950 (mdx‐T), a highly potent, specific, small-molecule inhibitor of NLRP3, and compared with untreated (mdx) and wild-type (WT) mice. In vivo functional tests were carried out to measure the global force and endurance of mice. Ex vivo biochemical and molecular analyses were performed to evaluate the pathophysiology of the skeletal muscle. Finally, in vitro tests were conducted on primary cultures of DMD human myotubes. Results: After MCC950 treatment, mdx mice exhibited a significant reduction of inflammation, macrophage infiltration and oxidative stress (-20 to -65%, P<0.05 vs untreated mdx). Mdx‐T mice displayed considerably less myonecrosis (-54%, P<0.05 vs mdx) and fibrosis (-75%, P<0.01 vs mdx). Moreover, a more mature myofibre phenotype, characterized by larger-sized fibres and higher expression of mature myosin heavy chains 1 and 7 was observed. Mdx-T also exhibited enhanced force and resistance to fatigue (+20 to 60%, P<0.05 or less). These beneficial effects resulted from MCC950 inhibition of both active caspase-1 (-46%, P=0.075) and cleaved gasdermin D (N-GSDMD) (-42% in medium-sized-fibres, P<0.001). Finally, the anti-inflammatory action and the anti-pyroptotic effect of MCC950 were also recapitulated in DMD human myotubes. Conclusion: Specific inhibition of the NLRP3 inflammasome can significantly attenuate the dystrophic phenotype. A novel finding of this study is the overactivation of GSDMD, which is hampered by MCC950. This ultimately leads to less inflammation and pyroptosis and to a better muscle maturation and function. Targeting NLRP3 might lead to an effective therapeutic approach for a better management of DMD.Fund for Scientific Research de Bélgica (FNRS)-PDR/T.0026.2

Belonging to a diabetes patients' association is predictive of better metabolic control

Aim. - Diabetes mellitus (DM) management requires the patient's involvement, but it is unknown whether belonging to a patient's association leads to better metabolic control. Methods. - A total of 323 type 1 (T1) and 494 type 2 (T2) outpatient diabetics were analyzed according to whether or not they were members of it diabetes patients' association. Results. -T1 members (M: N=138) were older and had longer diabetes durations than non-members (nM; N= 185). Both groups had similar BP, kidney function, lipid profile. BMI and socioeducational status. HbA(1c) (means +/- SD) were lower in M than in nM: 8.1 +/- 1.2% versus 8.4 +/- 1.4%, respectively; P<0.04. T1 M practised more frequent self-monitoring of blood glucose (SMBG). T2 M (N=97) were also older and had longer diabetes durations than nM (N=397), and both groups had similar BP, kidney function, BMI and socioeducational status. Although M had lower HOMA beta-cell function (50.6 +/- 31.5% versus 63.5 +/- 44.3% P<0.01), they had a similar HbA(1c) and a better lipid profile. T2 M practised more frequent SMBG and were more likely to use insulin. Oral antidiabetic, anti hypertensive and dyslipidaemic drug use was also similar, except fora higher use of calcium-channel blockers in T2 M. Conclusion. - Belonging to a patients' organization was associated with better HbA(1c) in T1DM. In T2DM, which progresses relentlessly, similar HbA(1c) levels and better lipid profiles were observed, despite longer known disease durations and lower beta-cell function. These were not explained by gender. clinical. renal. therapeutic or educational parameters, but might reflect more responsibility, empowerment and/or compliance in terms of the condition or its management. (C) 2008 Published by Elsevier Masson SAS