Julian P H Wong, Yaan-Kit Ng, Jeppe Kjærgaard, Ronnie Blazev, Atul S Deshmukh, Benjamin L Parker
{"title":"Skeletal muscle proteomics: considerations and opportunities.","authors":"Julian P H Wong, Yaan-Kit Ng, Jeppe Kjærgaard, Ronnie Blazev, Atul S Deshmukh, Benjamin L Parker","doi":"10.1038/s44324-025-00073-2","DOIUrl":"10.1038/s44324-025-00073-2","url":null,"abstract":"<p><p>Skeletal muscle accounts for 30-40% of body weight and plays an indispensable role in maintaining movement and is also a central regulator of whole-body metabolism. As such, understanding the molecular mechanisms of skeletal muscle health and disease is vital. Proteomics has been revolutionized in recent years and provided new insights into skeletal muscle. In this review, we first highlight important considerations unique to the field which make skeletal muscle one of the most challenging tissues to analyse by mass spectrometry. We then highlight recent advances using the latest case studies and how this has allowed coverage of the skeletal muscle temporal, fibre type and stem cells proteome. We also discuss how exercise and metabolic dysfunction can remodel the muscle proteome. Finally, we discuss the future directions of the field and how they can be best leveraged to increase understanding of human biology.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"30"},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12222842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Complex interaction of waist circumference, cardiometabolic markers, and sex on elderly mortality: a cohort study of 0.4 million UK adults.","authors":"Jingyi Wu, Pengfei Li, Shaomei Shang","doi":"10.1038/s44324-025-00075-0","DOIUrl":"10.1038/s44324-025-00075-0","url":null,"abstract":"<p><p>This prospective cohort study included 408,760 older adults to investigate complex interaction between waist circumference (WC), blood glucose (BG) or blood pressure (BP), and sex in relation to elderly mortality. We used Cox regression models incorporating a tensor product interaction function to model joint impacts of WC and four cardiometabolic markers on mortality, and developed a two-dimensional exposure-response function (ERF) to quantify the population adaptability to cardiometabolic dysfunction across different WC levels. The linear and nonlinear effects of BG and BP on mortality varied by WC, with significant synergistic interactions. The two-dimensional ERF quantified variations in excess mortality risk across different WC and cardiometabolic marker combinations. Individuals with higher WC exhibited a forward shift in risk thresholds, indicating reduced adaptability to elevated BG and BP levels. Our findings highlight the need for targeted cardiometabolic health management strategies to enhance adaptability and reduce the burden of cardiometabolic diseases in aging populations.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"31"},"PeriodicalIF":0.0,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christian N Cramer, František Hubálek, Christian Lehn Brand, Hans Helleberg, Peter Kurtzhals, Jeppe Sturis
{"title":"Publisher Correction: Chain splitting of insulin: an underlying mechanism of insulin resistance?","authors":"Christian N Cramer, František Hubálek, Christian Lehn Brand, Hans Helleberg, Peter Kurtzhals, Jeppe Sturis","doi":"10.1038/s44324-025-00076-z","DOIUrl":"10.1038/s44324-025-00076-z","url":null,"abstract":"","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"28"},"PeriodicalIF":0.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Khalishah Yusri, Sandra Jose, Karen S Vermeulen, Trina Chia Min Tan, Vincenzo Sorrentino
{"title":"The role of NAD<sup>+</sup> metabolism and its modulation of mitochondria in aging and disease.","authors":"Khalishah Yusri, Sandra Jose, Karen S Vermeulen, Trina Chia Min Tan, Vincenzo Sorrentino","doi":"10.1038/s44324-025-00067-0","DOIUrl":"10.1038/s44324-025-00067-0","url":null,"abstract":"<p><p>Nicotinamide adenine dinucleotide (NAD<sup>+</sup>) is a coenzyme involved in a plethora of physiological reactions, with a key relevance in supporting mitochondrial function. Due to its critical role in these cellular processes, declining levels of NAD<sup>+</sup> are associated with general aging and chronic disorders, including cognitive decline, sarcopenia, and metabolic diseases. These conditions are also typified by loss of mitochondrial health through dysfunction of homeostatic components such as mitophagy, unfolded protein response, and the antioxidant system. Therefore, raising cellular NAD<sup>+</sup> through vitamin B3 family precursors or via drug-based interventions has become a broadly used strategy to restore mitochondrial and organismal homeostasis, with NAD<sup>+</sup> precursors becoming a popular supplementation approach. As increasing components of the NAD<sup>+</sup> biology are unraveled, this comprehensive review summarizes the advances in mechanisms of NAD<sup>+</sup> metabolism and its modulation via compound-based strategies. Furthermore, it highlights the role of NAD<sup>+</sup> in mitochondrial homeostasis in aging and disease conditions, the latest results of NAD<sup>+</sup>-boosting therapeutics in clinical trials, and areas of further translational development.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"26"},"PeriodicalIF":0.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Valentina Trimarco, Raffaele Izzo, Daniela Pacella, Maria Virginia Manzi, Stanislovas S Jankauskas, Paola Gallo, Francesco Rozza, Giuseppe Giugliano, Alessandra Spinelli, Giovanni Esposito, Roberto Piccinocchi, Gaetano Piccinocchi, Carmine Morisco, Maria Lembo, Gaetano Santulli, Bruno Trimarco
{"title":"Aspirin reduces the risk of type 2 diabetes associated with COVID-19.","authors":"Valentina Trimarco, Raffaele Izzo, Daniela Pacella, Maria Virginia Manzi, Stanislovas S Jankauskas, Paola Gallo, Francesco Rozza, Giuseppe Giugliano, Alessandra Spinelli, Giovanni Esposito, Roberto Piccinocchi, Gaetano Piccinocchi, Carmine Morisco, Maria Lembo, Gaetano Santulli, Bruno Trimarco","doi":"10.1038/s44324-025-00072-3","DOIUrl":"10.1038/s44324-025-00072-3","url":null,"abstract":"<p><p>This study aimed to determine whether daily low-dose aspirin reduces the risk of type 2 diabetes (T2D) associated with COVID-19. A longitudinal cohort of 200,000 adults followed from 2018 to 2022 was analyzed, comparing T2D incidence between aspirin users and non-users. Propensity score matching was used to balance the groups. The incidence of T2D was substantially lower in the aspirin group, with Cox regression showing a 52% risk reduction. Kaplan-Meier analysis confirmed a significant divergence in cumulative T2D risk after two years. This protective effect was observed both before and during the COVID-19 pandemic, with a stronger association during the pandemic period. These findings indicate that daily low-dose aspirin significantly reduces the risk of COVID-19-associated new-onset T2D, highlighting the role of inflammation in the pathogenesis of T2D triggered or unmasked by COVID-19.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"27"},"PeriodicalIF":0.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12177057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alejandro E Mayorca-Guiliani, Diana Julie Leeming, Kim Henriksen, Joachim Høg Mortensen, Signe Holm Nielsen, Quentin M Anstee, Arun J Sanyal, Morten A Karsdal, Detlef Schuppan
{"title":"ECM formation and degradation during fibrosis, repair, and regeneration.","authors":"Alejandro E Mayorca-Guiliani, Diana Julie Leeming, Kim Henriksen, Joachim Høg Mortensen, Signe Holm Nielsen, Quentin M Anstee, Arun J Sanyal, Morten A Karsdal, Detlef Schuppan","doi":"10.1038/s44324-025-00063-4","DOIUrl":"https://doi.org/10.1038/s44324-025-00063-4","url":null,"abstract":"<p><p>Imperfect attempts at organ repair after repeated injury result in aberrant formation of extracellular matrix (ECM) and loss of tissue structure. This abnormal ECM goes from being a consequence of cellular dysregulation to become the backbone of a persistently fibrotic cell niche that compromises organic function and ultimately drives systemic disease. Here, we review our current understanding of the structure of the ECM, the mechanisms behind organ-specific fibrosis, resolution, healing and regeneration, as well as the development of anti-fibrotic strategies. We also discuss the design of biomarkers to investigate fibrosis pathophysiology, track fibrosis progression, systemic damage, and fibrosis resolution.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"25"},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mechanisms and implications of the gut microbial modulation of intestinal metabolic processes.","authors":"Jyoti, Priyankar Dey","doi":"10.1038/s44324-025-00066-1","DOIUrl":"https://doi.org/10.1038/s44324-025-00066-1","url":null,"abstract":"<p><p>Intestine-exclusive metabolic processes involve the degradation of dietary components and xenobiotics through intricate and dynamic interactions between the host epithelial cells and gut microbiota. Disruptions in this fragile equilibrium lead to metabolic and gastrointestinal diseases, highlighting the profound impact of the gut microbiota on the host intestinal metabolic processes. Gut microbes play a crucial role in influencing intestinal metabolic homeostasis by affecting nutrient sensing, gut hormones, neurotransmitters, and redox balance, collectively modulating mucosal gene expression and metabolic signaling pathways. These intestinal-level host-microbe metabolic interactions profoundly impact extra-intestinal tissues and organs. This comprehensive review provides mechanistic insights on the crucial role of gut microbiota in sustaining metabolic health by narrowing down to the gut-level metabolic interactions.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"24"},"PeriodicalIF":0.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bridget Chalifour, Elizabeth A Holzhausen, Joseph J Lim, Emily N Yeo, Natalie Shen, Dean P Jones, Bradley S Peterson, Michael I Goran, Donghai Liang, Tanya L Alderete
{"title":"Author Correction: The potential role of early life feeding patterns in shaping the infant fecal metabolome: implications for neurodevelopmental outcomes.","authors":"Bridget Chalifour, Elizabeth A Holzhausen, Joseph J Lim, Emily N Yeo, Natalie Shen, Dean P Jones, Bradley S Peterson, Michael I Goran, Donghai Liang, Tanya L Alderete","doi":"10.1038/s44324-025-00071-4","DOIUrl":"https://doi.org/10.1038/s44324-025-00071-4","url":null,"abstract":"","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"23"},"PeriodicalIF":0.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peter Aldiss, Malte Hasle Nielsen, Hayley Burm, Denise Oró, Henrik H Hansen, Michael Feigh, Matthew P Gillum
{"title":"FGF21 deletion mildly exacerbates hepatic dysfunction in GAN diet and alcohol fed rats.","authors":"Peter Aldiss, Malte Hasle Nielsen, Hayley Burm, Denise Oró, Henrik H Hansen, Michael Feigh, Matthew P Gillum","doi":"10.1038/s44324-025-00062-5","DOIUrl":"https://doi.org/10.1038/s44324-025-00062-5","url":null,"abstract":"<p><p>Fibroblast growth factor 21 (FGF21) analogues are in clinical development as treatments for metabolic and alcohol-associated liver disease. The aim of this study was to characterize the first FGF21 knockout (KO) rat line to validate its utility as a translational animal model that recapitulates human disease. We generated an FGF21 KO rat model and exposed 6-month-old WT and KO rats to either chow (n = 8 per genotype) or the obesogenic GAN (Gubra Amylin NASH) diet (n = 16 per genotype) for 12 weeks. Lack of endogenous FGF21 increased plasma transaminases, liver weight, and total levels of liver TG in GAN-fed FGF21 KO rats. FGF21 KO had no impact on body weight, glycaemic traits, or MASH histological endpoints, including hepatic steatosis, NAS score, lobular inflammation, ballooning degeneration, fibrosis stage, or the liver transcriptome. Finally, we demonstrate that endogenous FGF21 does not regulate drinking behaviour in rats.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 1","pages":"21"},"PeriodicalIF":0.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144556403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ivar van Galen, Maria B Birkisdóttir, Rutger A Ozinga, Renata M C Brandt, Sander Barnhoorn, Sandra Imholz, Conny T van Oostrom, Ricfrid W G N van der Marel, Kimberly Smit, Yvonne M A Rijksen, Erwin Reiling, Harry van Steeg, Jan H J Hoeijmakers, Martijn E T Dollé, Wilbert P Vermeij
{"title":"High protein intake causes gene-length-dependent transcriptional decline, shortens lifespan and accelerates ageing in progeroid DNA repair-deficient mice.","authors":"Ivar van Galen, Maria B Birkisdóttir, Rutger A Ozinga, Renata M C Brandt, Sander Barnhoorn, Sandra Imholz, Conny T van Oostrom, Ricfrid W G N van der Marel, Kimberly Smit, Yvonne M A Rijksen, Erwin Reiling, Harry van Steeg, Jan H J Hoeijmakers, Martijn E T Dollé, Wilbert P Vermeij","doi":"10.1038/s44324-025-00064-3","DOIUrl":"10.1038/s44324-025-00064-3","url":null,"abstract":"<p><p>Dietary composition can significantly influence health and lifespan, however, robust knowledge on which food components, at what concentration exert which long-term health effects is still incomplete. Here, we explored the effects of dietary protein intake on <i>Ercc1</i> <sup>Δ/-</sup> DNA-repair-deficient mice, which are an excellent model for accelerated ageing and are hyperresponsive to the anti-ageing effect of dietary restriction. Restricting dietary protein by 50% extended lifespan in male mice, but not in females. Restricting protein levels beyond 80% improved various neurological health parameters, while a further reduction to 95% affected appetite and became distinctly detrimental. Conversely, a near doubling of protein intake and isocaloric compensatory lowering with carbohydrates significantly shortened lifespan in both sexes. Gene expression analysis of liver from mice on a high-protein, low-carbohydrate diet to those on high-carbohydrate, low-protein revealed increased expression of oxidative phosphorylation, enrichment of processes associated with tissue injury, inflammation, and gene-length-dependent transcriptional decline (GLTD), recently shown to reflect DNA damage accumulation causing transcription stress, and cellular ageing. Finally, GLTD was also identified by reanalysis of publicly available data of wild-type mice, rats and humans on high-protein diets, suggesting that increased dietary protein enhances GLTD and accelerates systemic ageing. Together, our findings have implications for nutritional guidelines for progeroid DNA-repair-deficient human syndromes, warrant the use of excessive protein intake for sustaining health, and suggests GLTD as a sensitive read-out of overall health and predictor of biological ageing.</p>","PeriodicalId":501710,"journal":{"name":"npj Metabolic Health and Disease","volume":"3 ","pages":"20"},"PeriodicalIF":0.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098121/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}