Idiopathic inflammatory myopathies (IIMs) are severe autoimmune diseases with poorly understood pathogenesis and unmet medical needs. Here, we examine the role of interferon γ (IFNγ) using NOD female mice deficient in the inducible T cell co-stimulator (Icos), which have previously been shown to develop spontaneous IFNγ-driven myositis mimicking human disease. Using muscle proteomic and spatial transcriptomic analyses we reveal profound myofiber metabolic dysregulation in these mice. In addition, we report muscle mitochondrial abnormalities and oxidative stress in diseased mice. Supporting a pathogenic role for oxidative stress, treatment with a reactive oxygen species (ROS) buffer compound alleviated myositis, preserved muscle mitochondrial ultrastructure and respiration, and reduced inflammation. Mitochondrial anomalies and oxidative stress were diminished following anti-IFNγ treatment. Further transcriptomic analysis in IIMs patients and human myoblast in vitro studies supported the link between IFNγ and mitochondrial dysfunction observed in mice. These results suggest that mitochondrial dysfunction, ROS and inflammation are interconnected in a self-maintenance loop, opening perspectives for mitochondria therapy and/or ROS targeting drugs in myositis.

Objective: Inflammatory myopathies (IM), characterized by muscle inflammation and weakness, are rare systemic diseases. Our previous study estimated an IM incidence rate of 7.98 cases per million people per year (95% confidence interval 7.38–8.66) and highlighted important variations that were likely because of methodologic issues rather than true epidemiologic differences. In this study, we aimed to refine the incidence of IM, using the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for IM and a quadruple‐source capture–recapture method during a 6‐year period in Alsace, France, a region with a population of 2 million having benefits of good access to health care and accredited IM referral centers.Methods: Clinical data of potential IM patients were obtained from 4 sources (general practitioners and community specialists, public and private hospital records, public and private laboratories, and archives from the pathology department). Patients residing in Alsace and who fulfilled the 2017 EULAR/ACR criteria for IM between January 1, 2006, and January 1, 2013, were included. We corrected potentially incomplete ascertainment of cases with capture–recapture analyses. We studied both spatial and temporal distributions of incidence of IM. We also assessed systemic manifestations of the disease.Results: Our review of 1,742 potential cases identified 106 patients with IM. No spatial or temporal heterogeneity was observed. Use of log‐linear models showed an estimated 14.9 additional missed cases. Thus, the incidence rate of IM was 8.22 new cases per million inhabitants per year (95% confidence interval 6.76–9.69). Extramuscular manifestations other than dermatomyositis rash were frequently recorded.Conclusion: The stringent methodology used in our study provides an accurate estimation of the incidence of IM. This study also demonstrates, in a population‐based cohort, the systemic nature of IM. image

COVID-19 is a public health issue with a significant mortality rate and potential long-lasting disabling symptoms responsible for the long-COVID syndrome. Mitochondrial dysfunction is a key mechanism but whether peripheral blood mononuclear cell (PBMC) mitochondrial respiration changes might be associated with mortality and/or occurrence and severity of long-COVID syndrome remains to be investigated. We determined mitochondrial respiratory chain oxygen consumption in twenty COVID-19 patients hospitalized in the intensive care unit and analyzed their remaining symptoms at the third year after hospital release. PBMC mitochondrial respiration was decreased in COVID-19 patients compared to the control group (14.13 ± 2.35 vs. 6.21 ± 0.88 pmol/s/10⁶ cell, p = 0.0006 for the OXPHOS state by CII). Considering COVID severity, such a decrease was greater in long-COVID patients and in patients who deceased (4.91 ± 0.75, p = 0.008 and 4.94 ± 1.11 pmol/s/10⁶ cell, p = 0.04, respectively). PBMC markers of inflammation also increased with the severity of COVID (1.0 ± 0.08 vs. 14.45 ± 2.07, p = 0.02 for ISG15 in patients who died) and ISG15 negatively correlated with PBMC mitochondrial respiration (r = −0.67, p = 0.02 for CII). In conclusion, this study shows that the greater the impairment in PBMC mitochondrial respiration in patients hospitalized in the intensive care unit for COVID-19, the greater the mortality rate and the more severe the long-COVID symptoms—three years after hospital discharge. Further, PBMC markers of inflammation also increased with the severity of COVID and ISG15 negatively correlated with PBMC mitochondrial respiration. These results support that PBMC mitochondrial respiration might be a biomarker of COVID severity and further studies investigating whether modulation of PBMC mitochondrial respiration might improve COVID-19 patients’ prognosis.

Weight cycling is a major challenge in obesity management. Caloric restriction is known to promote this phenomenon, but the impact of macronutrient changes during dieting remains unclear. This study aimed to determine the role of macronutrient changes in weight maintenance without caloric restriction by alternating between two hypercaloric diets: a high-carbohydrate, high-fat Western diet (WD) and a low-carbohydrate, high-fat diet (LCHDF). Obesity was induced in 8-week-old C57BL/6 male mice by 10 weeks of WD feeding. Then, the mice were subjected to 12 weeks of LCHFD interspersed with WD (I-WD), 3 periods of 2-week LCHFD followed by 2 periods of 3-week WD, or 12 weeks of continuous WD (C-WD). C-WD and I-WD mice were compared to standard diet (SD) mice. In the I-WD group, each LCHFD period decreased weight gain, but mice regained weight after WD resumption. I-WD mice exhibited obesity, dyslipidemia, and glucose intolerance, similarly to the C-WD mice. I-WD mice also developed nonalcoholic steatohepatitis, associated with an increase in type-III collagen gene expression and a decrease in FGF21 protein levels, in comparison with SD. I-WD mice developed weight cycling despite maintaining a high caloric consumption, suggesting that changes in macronutrients during dieting are also a trigger of weight regain.

Obesity is associated with a low-grade inflammation, characterized by the secretion of inflammatory mediators, that contribute to non-alcoholic fatty liver disease (NAFLD) development. Steatosis may be complicated by hepatocellular injury and liver inflammation (steatohepatitis or NASH). Ketogenic diet (KD), a high-fat and low-carbohydrate diet, seems to present anti-inflammatory properties which could reduce NAFLD development. However, the mechanisms involved in its beneficial effects remain unclear. Obesity was induced in C57/Bl6 mice (n = 20) by using a high-fat, high-sugar diet (HFD). After 16 weeks of HFD, mice were split into two groups for six weeks: KD mice (n = 10) and HFD mice (n = 10). At the end of the 22-week protocol, we measured liver weight, hepatic lipid accumulation and inflammatory infiltrates with histological staining, and hepatic gene expression by RT-qPCR. Both HFD and KD were isocaloric and compared with a control diet (Ctrl) group of mice (n = 10). After 22 weeks of HFD, mice developed obesity (+82% of weight gain, p < 0.001) associated with an increase in liver weight (+113%, p < 0.001) and hepatic lipid accumulation (+158%, p < 0.001), compared with Ctrl. RT-qPCR revealed an increase in TNFa (p < 0.05), IL-1 (p < 0.05) and collagen 1 (p < 0.01) gene expression, but no changes of IL-10, TGFb and IFNg, compared to Ctrl. Histological staining showed an important steatosis and inflammatory infiltrates. Compared to HFD, six weeks of KD allow to reduce the liver weight (−31%, p < 0.01), reduce steatosis and ballooning hepatocytes, and decreased IL-6 (p < 0.05) and collagen 1 (p < 0.05) gene expression. However, KD had no effect on IL-1, TNFa, IFNg, IL-10 gene expression, compared to HFD. These results suggest that in a context of hypercaloric diet and NAFLD development, replacing sugar by lipids is efficient to prevent the onset of NASH at least partly due to a reduction in lipid accumulation and hepatocellular injuries.