Biology subjects

Schuermann, A.

Publications and source records attributed to Schuermann, A..

6 recordsLinked to original sources

bioRxiv2026

Damage sensing recruitment of a lipid phosphatase couples lysosomal membrane repair to proteostatic adaptation

Restoration of organellar membrane integrity is critical for maintaining cellular homeostasis. Lysosomal membrane damage activates local repair machineries and global stress responses, but how signaling lipid metabolism is engaged by damage sensors to support and mechanistically link these processes remains poorly understood. Here we show that the phosphoinositide 3-phosphatase MTMR14 is recruited to damaged lysosomes through calcium-dependent binding to sphingomyelin. At these sites, MTMR14 promotes local PI(3)P hydrolysis and supports PI(4)P accumulation, thereby facilitating formation of ER-lysosome contact sites associated with membrane repair, without affecting ESCRT recruitment. MTMR14-dependent lipid remodelling causes reduced mTORC1 signalling and a decrease in global protein synthesis, consistent with an acute proteostatic adaptation to lysosomal injury. Cells lacking MTMR14 display impaired damage-induced lipid remodelling, altered repair-associated structures, sustained protein synthesis, and increased sensitivity to lysosomal injury, all of which can be mitigated by mTORC1/S6K inhibition. Our findings identify damage-sensing recruitment of MTMR14 and local PI(3)P turnover on damaged lysosomes as a phosphoinositide module that promotes lysosomal membrane integrity and homeostasis while functionally linking nutrient signalling to proteostasis under membrane stress.

cell biology↗

bioRxiv2025

Nutritional hyperketonemia by dietary medium-chain fatty acids is driven by the liver without contribution from the intestine

Saturated medium-chain fatty acids (MCFAs) are ketogenic nutrients, and their dietary intake has been linked to health benefits such as improved energy balance and increased insulin sensitivity. Here, we tested the hypothesis that MCFA-mediated hyperketonemia is required for these benefits. Using tissue-specific 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) knockout mouse models, we show that the hyperketonemia induced by oral administration of triacylglycerols with the MCFA octanoic acid (C8:0-MCT) is mediated by hepatic, but not intestinal, ketogenesis. Remarkably, acute reductions in food intake and body weight induced by C8:0-MCT in obese mice were independent of hepatic ketogenesis; likewise, chronic protection against weight gain and marked improvements in insulin sensitivity elicited by MCFA-rich diets did not require hepatic ketogenesis. These data demonstrate that dietary MCFAs are potent bioactive lipids capable of inducing metabolic benefits independently of their ketogenic properties.

physiology↗

bioRxiv2024

Sexual dimorphism in molecular profiles of resting human skeletal muscle and the response to acute exercise and endurance training

Biological sex has a strong impact on skeletal muscle metabolism and performance. By a comprehensive investigation of epigenetic, transcriptomic and proteomic differences between female and male skeletal muscle of untrained subjects we provide a molecular basis for the sexual dimorphism of glucose and lipid metabolism. The sex-specific multi-OMICs profiles indicate higher degree of glucose turnover and higher abundance of fast-twitch fibers in males and high degree of lipid handling in females. Eight-week endurance training equalized initial differences toward an endurance-trained proteomic profile in both sexes. The untrained muscle of females was more resistant to an acute exercise challenge since stress-responsive transcripts were predominantly upregulated in males. In myotubes from the same donors, transcriptomic differences were hardly conserved, but could be partially restored by treatment with sex hormones. In conclusion, after only 8 weeks training mitigates deeply rooted sex-specific molecular profiles in skeletal muscle toward a common metabolically beneficial response.

biochemistry↗

bioRxiv2023

Aging impairs muscle regeneration by desynchronizing matrix mechano-signaling and macrophage immunomodulation via fibro-adipogenic progenitors

Skeletal muscle regeneration depends on the function of fibro/adipogenic progenitors (FAPs). Here we show that aging impairs myogenic stem cells by disrupting the integration of extracellular matrix and immunomodulatory functions within the stem cell niche, thereby promoting fibro/fatty degeneration. We identify the FAP-secreted protein Periostin as a niche factor that is decreased in aged muscle and in circulation of aged humans with low-exercise lifestyle. Periostin controls FAP-expansion after injury and its depletion fate-regulates FAPs towards adipogenesis. This leads to delayed pro- to anti-inflammatory macrophage transition during regeneration. Transplantation of young FAPs with high Periostin secretion, but not Periostin-deficient FAPs, into aged muscle restores inflammation resolution and successful regeneration. Mechanistically, Periostin activates Focal adhesion kinase- and AKT-signaling in macrophages via integrins to promote an anti-inflammatory profile, which synchronizes matrix-derived mechanosensory signaling and immunomodulation. These results uncover a novel role of FAP-based regulation that orchestrates successful muscle regeneration and prevents fibro/fatty degeneration.

physiology↗

bioRxiv2023

Pantothenate Kinase 4 controls efficient skeletal muscle energy substrate metabolism via acetyl-CoA

Metabolic inflexibility in skeletal muscle (SkM) is closely linked to metabolic diseases. Exercise improves metabolic flexibility, rendering it a valuable discovery tool of mechanisms promoting efficient metabolism of glucose and lipids. We herein discover pantothenate kinase 4 (PanK4) as a conserved exercise target with high abundance in SkM. We go on to show that murine muscle Pank4 is dysregulated with high-fat diet feeding, and identify human PANK4 variants that associate with glycemic control and body mass index traits, indicating important roles of PanK4 in glucose metabolism and growth. Consistent with the latter, germline deletion of PanK4 reduces circulating IGF-1 and stunts growth in mice. Deletion specifically in mouse SkM reveals that PanK4 facilitates fatty acid oxidation by acting as a regulator of SkM acetyl-CoA, a key node in metabolism of both glucose and lipids. Consequently, without PanK4, elevated SkM acetyl-CoA levels allosterically gridlock key enzymes required for efficient lipid and glucose utilization, and these SkM metabolic perturbations manifest in whole-body insulin resistance. As proof of principle, we show that an increase in muscle PanK4 lowers SkM acetyl-CoA and increases SkM glucose utilization. Our findings identify PanK4 as a novel regulator of SkM energy substrate metabolism, warranting inclusion in comprehensive strategies against metabolic disease.

physiology↗

bioRxiv2019

EHD2-mediated restriction of caveolar dynamics regulates cellular lipid uptake

Eps15-homology domain containing protein 2 (EHD2) is a dynamin-related ATPase located at the neck of caveolae, but its physiological function has remained unclear. We found that global genetic ablation of EHD2 in mice led to increased fat deposits in several organs. This organismic phenotype was paralleled at the cellular level by an increased lipid uptake via a CD36-dependent pathway, an elevated number of detached caveolae and higher caveolar mobility. Following a high fat diet, various enzymes involved in de novo fatty acid synthesis were down-regulated in EHD2 KO mice. Furthermore, EHD2 expression itself was down-regulated in the visceral fat of two obese mouse models and in diet-induced obesity. Thus, EHD2 controls a cell-autonomous, caveolae-dependent lipid uptake pathway, implicating a role of EHD2 in fat accumulation and obesity.

cell biology↗