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HomeCirculation ResearchVol. 132, No. 11In this Issue Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIn this Issue Originally published25 May 2023https://doi.org/10.1161/RES.0000000000000613Circulation Research. 2023;132:1425is related toEnhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle RemodelingMechanism of Tumor-Platelet Communications in CancerTranscriptomic and Proteomic of Gastrocnemius Muscle in Peripheral Artery DiseaseTranscriptomic and Proteomic of Gastrocnemius Muscle in Peripheral Artery Disease (p 1428)Download figureDownload PowerPointFerrucci et al identify dysregulated pathways in the muscles of peripheral artery disease patients.Peripheral artery disease (PAD) occurs when atherosclerosis causes narrowing of the blood vessels supplying the lower extremities. Aside from leg pain during walking, the hypoxia causes damage to the muscles and there are no effective remedies. To look for potential drug targets, Ferrucci and colleagues performed transcriptomics and proteomics on biopsy samples from calf muscles of 31 people with PAD and 29 people without. They compared more than 20,000 transcripts and 6,000 proteins and from computational analyses found that PAD patient muscles exhibited ramped up inflammation, hypoxia responses, apoptosis, fibrosis and angiogenesis. They also unexpectedly found that while levels of mitochondrial proteins were increased in PAD muscles, levels of the related transcripts were decreased. The authors suggest this apparent discrepancy may be due to regulatory feedback wherein accumulation of dysfunctional mitochondria inhibits transcription of the related genes. Indeed, in PAD samples, the abundance of mitochondrial proteins did not correlate with mitochondrial activity while it did in controls. Whatever the reason, the results provide a wealth of data to inform drug development efforts aimed at preserving muscle health in PAD.Mechanism of Tumor-Platelet Communications in Cancer (p 1447)Download figureDownload PowerPointCancer-derived extracellular vesicles drive platelet activation, show Dudiki et al.Thrombosis is a major, sometimes fatal, complication of cancer. But how and why platelets—the key cells controlling clotting—become activated in cancer isn’t clear. Cancer patient platelets are known to accumulate tumor-derived factors and tumors are known to secrete procoagulant vesicles. Now, Dudiki and colleagues have tied these two findings together, showing that tumor-derived extracellular vesicles (EVs) are taken up by platelets, wherein they activate the cells. And they have also identified the EV key to the platelet door. The team applied EVs to cultured mouse platelets and found those derived from tumors were taken up more readily than synthetic or fibroblast-derived ones. The tumor EVs, but not the synthetic or fibroblast-derived ones were also able to induce platelet activation. The uptake of EVs led to accumulation of certain cancer-specific factors in the platelets and this was also true in vivo—when mice were injected with tumor EVs or had tumors implanted. The team went on to show that blocking CD63—a major EV surface protein—prevented EV-induced platelet activation in culture and thrombus formation in mice. They thus conclude that CD63 could be a clinical target for life-saving anti-thrombosis treatments in cancer patients.Enhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle Remodeling (e171)Download figureDownload PowerPointEnhanced mitochondria-sarcoplasmic reticulum links improve heart resilience, say Nichtova et al.In cardiomyocytes, the sarcoplasmic reticulum (SR) is closely associated with mitochondria enabling calcium released by the former to enter the latter to power ATP production—known as excitation-bioenergetics coupling (EBC). Proteins tethers hold the organelles in proximity, and acute overexpression of such tethers improves EBC and corrects heart contractile deficits in mice with cardiomyopathy. The effects of long-term enhanced tethering are unknown, however, and might even be detrimental—causing excess reactive oxygen species from over-stimulated mitochondria. Now Nichtova and colleagues examine such a cardiomyocyte-specific scenario in mice, engineering a mitochondrial-SR tether that is expressed in the animals from birth. In addition to enhanced SR-mitochondrial connections, the heart cells of the animals exhibited increased contractility, strong calcium signaling and good EBC. Furthermore, when subjected to ischemia and reperfusion, the test animals’ hearts showed better recovery of contractility, smaller infarct size and less myocyte death than control hearts. They were also more resilient to adrenergic stress. The results suggest that long-term tethering is not detrimental and may have therapeutic potential for improving heart recovery after injury. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesEnhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle RemodelingZuzana Nichtová, et al. Circulation Research. 2023;132:e171-e187Mechanism of Tumor-Platelet Communications in CancerTejasvi Dudiki, et al. Circulation Research. 2023;132:1447-1461Transcriptomic and Proteomic of Gastrocnemius Muscle in Peripheral Artery DiseaseLuigi Ferrucci, et al. Circulation Research. 2023;132:1428-1443 May 26, 2023Vol 132, Issue 11 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/RES.0000000000000613 Originally publishedMay 25, 2023 PDF download Advertisement