Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity

Özcan, Mualla; Guo, Zhen; Ripoll, Carla Valenzuela; Diab, Ahmed; Picataggi, Antonino; Rawnsley, David R.; Lotfinaghsh, Aynaz; Bergom, Carmen; Szymański, J.; Hwang, Daniel; Asnani, Aarti; Kosiborod, Mikhail; Jiao, Z.; Hayashi, Robert J.; Woodard, Pamela K.; Kovács, Attila; Margulies, Kenneth B.; Schilling, Joel D.; Razani, Babak; Diwan, Abhinav; Javaheri, Ali

doi:10.1016/j.cmet.2023.02.006

Cited by 37 publications

(14 citation statements)

References 40 publications

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“…GDF15 is a heart-derived biomolecule, 102 a cardiovascular biomarker candidate, 103 and is sufficient to cause cardiac atrophy. 104 Although our study was not designed to assess its biomarker potential, its potential instruction through circulating retained metabolites emphasizes its central role in body homeostasis and organ communication. 102 In essence, SGLT2i could affect the microbiome formation of uremic toxins as an unanticipated off-target mechanism with protective potential on the heart and kidney.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Communication by SGLT2 Inhibition

Billing,

Kim,

Gullaksen

et al. 2024

Circulation

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BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but the underlying mechanism remains poorly understood. METHODS: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or are secondary to improvement by SGLT2i, we performed an in-depth proteomics, phosphoproteomics, and metabolomics analysis by integrating signatures from multiple metabolic organs and body fluids after 1 week of SGLT2i treatment of nondiabetic as well as diabetic mice with early and uncomplicated hyperglycemia. RESULTS: Kidneys of nondiabetic mice reacted most strongly to SGLT2i in terms of proteomic reconfiguration, including evidence for less early proximal tubule glucotoxicity and a broad downregulation of the apical uptake transport machinery (including sodium, glucose, urate, purine bases, and amino acids), supported by mouse and human SGLT2 interactome studies. SGLT2i affected heart and liver signaling, but more reactive organs included the white adipose tissue, showing more lipolysis, and, particularly, the gut microbiome, with a lower relative abundance of bacteria taxa capable of fermenting phenylalanine and tryptophan to cardiovascular uremic toxins, resulting in lower plasma levels of these compounds (including p-cresol sulfate). SGLT2i was detectable in murine stool samples and its addition to human stool microbiota fermentation recapitulated some murine microbiome findings, suggesting direct inhibition of fermentation of aromatic amino acids and tryptophan. In mice lacking SGLT2 and in patients with decompensated heart failure or diabetes, the SGLT2i likewise reduced circulating p-cresol sulfate, and p-cresol impaired contractility and rhythm in human induced pluripotent stem cell–engineered heart tissue. CONCLUSION: SGLT2i reduced microbiome formation of uremic toxins such as p-cresol sulfate and thereby their body exposure and need for renal detoxification, which, combined with direct kidney effects of SGLT2i, including less proximal tubule glucotoxicity and a broad downregulation of apical transporters (including sodium, amino acid, and urate uptake), provides a metabolic foundation for kidney and cardiovascular protection.

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Section: Discussionmentioning

confidence: 99%

Metabolic Communication by SGLT2 Inhibition

Billing,

Kim,

Gullaksen

et al. 2024

Circulation

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“…It has also been shown that GDF15 expression increases in the heart as an anti-hypertrophic response during ischemic or pressure-overload related stress. Recently heart GDF15 was found to be maladaptively upregulated during doxorubicin treatment when combined with alternate-day fasting, a form of nutrient stress 40 . This work suggested that exogenous GDF15 was sufficient to confer cardiomyocyte atrophy in that model.…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte PGC-1α enables physiological adaptations to endurance exercise through suppression of GDF15 and cardiac atrophy

Khetarpal,

Li,

Vitale

et al. 2024

Preprint

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SummaryExercise training induces physiological cardiac hypertrophy, enhanced mitochondrial biogenesis and myocardial contractility. In skeletal muscle, the transcriptional coactivator PGC-1α is a key orchestrator of these responses. The heart expresses abundant and exercise-responsive PGC-1α, but it is unclear whether cardiomyocyte PGC-1α is necessary for cardiac adaptation to endurance training. Here we demonstrate that cardiomyocyte PGC-1α is required for physiological cardiac hypertrophy during exercise training in mice. In the absence of cardiomyocyte PGC-1α, voluntary wheel running does not improve exercise capacity and instead confers immune-fibrotic-atrophic heart failure after just 6 weeks of training. We identify cardiomyocyte PGC-1α as a negative regulator of stress-responsive senescence gene expression. The most enriched of these is the myomitokine GDF15. GDF15 is secreted locally but not systemically in PGC-1α-deficient mouse hearts and reduces cardiomyocyte size. Cardiomyocyte-specific reduction of GDF15 expression preserves exercise tolerance and cardiac contractility in PGC-1α-deficient mice during endurance training. Finally, we show that cardiomyocytePPARGC1Aexpression correlates with cardiomyocyte number and negatively with GDF15 expression in human cardiomyopathies through single nucleus RNA sequencing. Our data implicate cardiomyocyte PGC-1α as a vital safeguard against stress-induced atrophy and local GDF15-induced dysfunction during exercise.

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“…With the growing understanding of DIC, the intervention of inflammation [ 40 ] and autophagy [ 41 ], are constantly being updated. Recent advances in molecular biology have significantly expanded the scope of research on DOX cardiotoxicity.…”

Section: The Molecular Mechanism Of Dicmentioning

confidence: 99%

Role of gut microbiota in doxorubicin-induced cardiotoxicity: from pathogenesis to related interventions

Huang,

Li,

et al. 2024

J Transl Med

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Doxorubicin (DOX) is a broad-spectrum and highly efficient anticancer agent, but its clinical implication is limited by lethal cardiotoxicity. Growing evidences have shown that alterations in intestinal microbial composition and function, namely dysbiosis, are closely linked to the progression of DOX-induced cardiotoxicity (DIC) through regulating the gut-microbiota-heart (GMH) axis. The role of gut microbiota and its metabolites in DIC, however, is largely unelucidated. Our review will focus on the potential mechanism between gut microbiota dysbiosis and DIC, so as to provide novel insights into the pathophysiology of DIC. Furthermore, we summarize the underlying interventions of microbial-targeted therapeutics in DIC, encompassing dietary interventions, fecal microbiota transplantation (FMT), probiotics, antibiotics, and natural phytochemicals. Given the emergence of microbial investigation in DIC, finally we aim to point out a novel direction for future research and clinical intervention of DIC, which may be helpful for the DIC patients.

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Sustained alternate-day fasting potentiates doxorubicin cardiotoxicity

Cited by 37 publications

References 40 publications

Metabolic Communication by SGLT2 Inhibition

Metabolic Communication by SGLT2 Inhibition

Cardiomyocyte PGC-1α enables physiological adaptations to endurance exercise through suppression of GDF15 and cardiac atrophy

Role of gut microbiota in doxorubicin-induced cardiotoxicity: from pathogenesis to related interventions

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