Marie Lhomme

Aging reduces skeletal muscle regenerative capacity, but how the aged environment impairs muscle stem cells (MuSCs) remains unclear. Skeletal muscle acts as a secretory organ, yet age-related changes in its secretome and impact on stem cells are poorly understood. We performed proteomic and lipidomic analyses of conditioned media from primary muscle cells of young (15–25 years) and aged (60–86 years) donors. We identified 127 age-dependent secreted proteins, revealing major remodeling. The lysosomal enzyme acid sphingomyelinase (ASM), which converts sphingomyelin into ceramide, was the most upregulated factor. Recombinant ASM reduced PAX7+ MuSCs in young cultures, showing extracellular ASM impairs stem cell maintenance. Lipidomics revealed disruption of the sphingomyelin–ceramide–S1P axis, with decreased sphingomyelin and S1P, a lipid promoting MuSC proliferation. Exogenous S1P restored the stem cell pool in aged cultures. These findings link secretome remodeling and sphingolipid metabolism to MuSC decline and identify ASM and S1P as targets.

Fanconi anemia (FA) is characterized by defective DNA repair and chronic p53 activation, predisposing to acute myeloid leukemia through persistent genomic instability. The molecular adaptations enabling cell survival under chronic stress remain poorly understood. This study investigates the role of ZMAT3, a p53 responsive RNA binding protein overexpressed in FA deficient cells, to elucidate its role in cellular adaptation. Using FA patient fibroblasts and Fancg KO mouse models, we launched transcriptomic profiling, lipidomic, and functional analyses. RNA-seq and lipidomic analyses revealed unexpected alterations in sphingolipid metabolism upon ZMAT3 depletion, linked to ceramide accumulation and downregulation of ASAH1 (acid ceramidase). Functionally, ZMAT3 depletion increased DNA damage and enhanced ferroptosis susceptibility, an iron dependent cell death mechanism. Mechanistically, our results showed that ZMAT3 promotes ASAH1 expression, limits ceramide accumulation and protects cells from ferroptosis induced death which could participate to preleukemic clonal evolution and pointing to areas for further exploration in FA-associated malignancies.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with no effective curative therapies. Necroptosis, a regulated necrotic cell death pathway controlled by receptor-interacting protein kinase 1 (RIPK1), has emerged as a potential driver of inflammation and fibrosis in chronic liver disorders. We investigated the role of necroptosis in PSC and whether RIPK1 inhibition could modify disease course and progression. Spatial profiling of human PSC biopsies revealed that necroptosis primarily affects cholangiocytes, while apoptosis was more frequent in hepatocytes and nonbiliary cells. In vitro, necroptosis inhibition protected cholangiocytes, and RIPK1 deletion conferred resistance to TNF-mediated cytotoxicity. In a murine model of PSC, pharmacological RIPK1 inhibition reduced cholestatic injury, hepatic inflammation, and biliary fibrosis. Multiomic analyses comprehensively demonstrated reprogramming toward wild-type–like profiles following treatment. These findings identify necroptosis as a critical effector in PSC and highlight RIPK1 inhibition as a promising disease-modifying approach, opening the door to targeted necroptosis-based therapies for this otherwise untreatable disease.

The mechanisms governing adipose tissue macrophage (ATM) metabolic adaptation during diet-induced obesity (DIO) are poorly understood. In obese adipose tissue, ATMs are exposed to lipid fluxes, which can influence the activation of specific inflammatory and metabolic programs and contribute to the development of obesity-associated insulin resistance and other metabolic disorders. In the present study, we demonstrate that the membrane ATP-binding cassette g1 (Abcg1) transporter controls the ATM functional response to fatty acids (FAs) carried by triglyceride-rich lipoproteins, which are abundant in high-energy diets. Mice genetically lacking Abcg1 in the myeloid lineage presented an ameliorated inflammatory status in adipose tissue and reduced insulin resistance. Abcg1-deficient ATMs exhibited a less inflammatory phenotype accompanied by a low bioenergetic profile and modified FA metabolism. A closer look at the ATM lipidome revealed a shift in the handling of FA pools, including a redirection of saturated FAs from membrane phospholipids to lipid droplets, leading to a reduction in membrane rigidity and neutralization of proinflammatory FAs. ATMs from human individuals with obesity presented the same reciprocal relationship between ABCG1 expression and this inflammatory and metabolic status. Abolition of this protective, anti-inflammatory phenotype in Abcg1-deficient ATMs was achieved through restoration of lipoprotein lipase (Lpl) activity, thus delineating the importance of the Abcg1/Lpl axis in controlling ATM metabolic inflammation. Overall, our study identifies the rewiring of FA pools by Abcg1 as a major pathway orchestrating ATM plasticity and insulin resistance in DIO.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease caused by the loss of function mutations in the LCAT gene. LCAT deficiency is characterized by an abnormal lipoprotein profile with severe reduction in plasma levels of high-density lipoprotein (HDL) cholesterol and the accumulation of lipoprotein X (LpX). Renal failure is the major cause of morbidity and mortality in FLD patients; the pathogenesis of renal disease is only partly understood, but abnormalities in the lipoprotein profile could play a role in disease onset and progression. Serum and lipoprotein fractions from LCAT deficient carriers and controls were tested for renal toxicity on podocytes and tubular cells, and the underlying mechanisms were investigated at the cellular level. Both LpX and HDL from LCAT-deficient carriers triggered oxidative stress in renal cells, which culminated in cell apoptosis. These effects are partly explained by lipoprotein enrichment in unesterified cholesterol and ceramides, especially in the HDL fraction. Thus, alterations in lipoprotein composition could explain some of the nephrotoxic effects of LCAT deficient lipoproteins on podocytes and tubular cells.

Metabolic disorders such as obesity are risk factors of atrial fibrillation, not only by sharing comorbidities but likely through their direct impact on atria, notably its adipogenicity. Here, we submitted mice that lack cardiac adipose tissue to a high fat diet and first studied the atrial metabolomic and lipidomic phenotypes using liquid chromatography-mass spectrometry. We found an increased consumption of free fatty acid by the beta-oxidation and an accumulation of long-chain lipids in atria of obese mice. Free fatty acid was the main substrate of mitochondrial respiration studied in the saponin-permeabilized atrial muscle. Conducted action potential recorded in atrial trabeculae was short, and ATP-sensitive potassium current was increased in perforated patch-clamp atrial myocytes of obese mice. There was histological and phenotypical evidence for an accumulation of adipose tissue in obese mice atria. Thus, an obesogenic diet transforms the energy metabolism, causes fat accumulation and induces electrical remodeling of atria myocardium. HIGHLIGHTS - Untargeted metabolomic and lipidomic analysis revealed that a high fat diet induces profound transformation of atrial energy metabolism with beta-oxidation activation and long-chain lipid accumulation. - Mitochondria respiration studied in atrial myocardial trabecula preferentially used Palmitoyl-CoA as energy substrate in obese mice. - Atria of obese mice become vulnerable to atrial fibrillation and show short action potential due to the activation of K-ATP dependent potassium current. - Adipocytes and fat molecular markers were detected in atria of obese mice together with an inflammatory profile consistence with a myocardial accumulation of fat.