A NRF2/beta3-adrenoreceptor axis drives a sustained antioxidant and metabolic rewiring through the pentose-phosphate pathway to alleviate cardiac stress

Michel, L.; Esfahani, H.; Verdoy, R.; de Mulder, D.; Ambroise, J.; Roelants, V.; Bouchard, B.; Savary, J.; Dewulf, J.; Doumont, T.; Bouzin, C.; Haufroid, V.; Luiken, J. J. F. P.; Nabben, M.; Singleton, M.; Bertrand, L.; Ruiz, M.; Des Rosiers, C.; Balligand, J.-L.

doi:10.1101/2023.11.10.564735

bioRxiv · 10.1101/2023.11.10.564735

A NRF2/beta3-adrenoreceptor axis drives a sustained antioxidant and metabolic rewiring through the pentose-phosphate pathway to alleviate cardiac stress

Michel, L.·Esfahani, H.·Verdoy, R.·de Mulder, D.·Ambroise, J.·Roelants, V.·Bouchard, B.·Savary, J.·Dewulf, J.·Doumont, T.·Bouzin, C.·Haufroid, V.·Luiken, J. J. F. P.·Nabben, M.·Singleton, M.·Bertrand, L.·Ruiz, M.·Des Rosiers, C.·Balligand, J.-L.

View original source ↗Export metadata ↓

Abstract

BackgroundCardiac {beta}3-adrenergic receptors ({beta}3AR) are upregulated in diseased hearts and mediate antithetic effects to those of {beta}1AR and {beta}2AR. {beta}3AR agonists were recently shown to protect from myocardial remodeling in preclinical studies and to improve systolic function in patients with severe heart failure. The underlying mechanisms, however, remain elusive. MethodsTo dissect functional, transcriptional and metabolic effects, hearts and isolated ventricular myocytes from mice harboring a moderate, cardiac-specific expression of a human ADRB3 transgene ({beta}3AR-Tg) and subjected to transverse aortic constriction (TAC) were assessed using echocardiography, RNAseq, PET scan, metabolomics, seahorse and metabolic flux analysis. Subsequently, signaling and metabolic pathways were investigated further in vivo in {beta}3AR-Tg and in vitro in neonatal rat ventricular myocytes adenovirally infected to express {beta}3AR and subjected to neurohormonal stress. These results were completed with an analysis of single nucleus RNAseq data from human cardiac myocytes from heart failure patients. ResultsCompared with WT littermate, {beta}3AR-Tg mice were protected from hypertrophy after transaortic constriction (TAC), while systolic function was preserved. {beta}3AR-expressing hearts displayed enhanced myocardial glucose uptake under stress in absence of increased lactate levels. Instead, metabolomic and metabolic flux analyses in stressed hearts revealed an increase in intermediates of the Pentose-Phosphate Pathway (PPP) in {beta}3AR-Tg, an alternative route of glucose utilization, paralleled with increased transcript levels of NADPH-producing and rate-limiting enzymes of the PPP, without fueling the hexosamine metabolism. The ensuing increased content of NADPH and of reduced glutathione decreased myocyte oxidant stress, while downstream oxidative metabolism assessed by oxygen consumption was preserved with higher glucose oxidation in {beta}3AR-Tg post-TAC compared to WT, together with increased mitochondrial biogenesis. Unbiased transcriptomics and pathway analysis identified NRF2 (NFE2L2) as upstream transcription factor which was functionally verified in {beta}3AR-expressing cardiac myocytes where its translocation and nuclear activity was dependent on {beta}3AR activation of nitric-oxide synthase (NOS) NO production. ConclusionModerate expression of cardiac {beta}3AR, at levels observed in human cardiac myocardium, exerts antioxidant effects through activation of the PPP and NRF2 pathway, thereby preserving myocardial oxidative metabolism, function and integrity under pathophysiological stress.

Source connections

Published article ↗

Explore related subjects

physiology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Michel, L., Esfahani, H., Verdoy, R., de Mulder, D., Ambroise, J., Roelants, V., Bouchard, B., Savary, J., Dewulf, J., Doumont, T., Bouzin, C., Haufroid, V., Luiken, J. J. F. P., Nabben, M., Singleton, M., Bertrand, L., Ruiz, M., Des Rosiers, C., Balligand, J.-L.. 2023-11-14. A NRF2/beta3-adrenoreceptor axis drives a sustained antioxidant and metabolic rewiring through the pentose-phosphate pathway to alleviate cardiac stress. https://doi.org/10.1101/2023.11.10.564735

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Skeletal muscle aging drives sex- and compartment-specific protein insolubility that is modifiable by proteostasis-directed treatments

Protein aggregation and altered protein solubility indicate proteostatic decline, yet their roles in skeletal muscle aging remain poorly understood. We combined light and electron microscopy, quantitative proteomics, and stable-isotope labeling of skeletal muscle to investigate age-associated changes in protein insolubility, and their responses to exercise and rapamycin. Aged muscle accumulated distinct aggresome and amyloid-positive aggregates despite unchanged bulk insoluble protein content. Instead, aging altered the abundance and soluble-insoluble shifts of lower-abundance proteins across cellular components, particularly mitochondrial, nuclear and extracellular matrix proteins, with greater changes in females. These changes were not broadly explained by intrinsic protein aggregation propensity. Exercise and rapamycin partially reversed age-associated changes in abundance and partitioning without increasing protein synthesis. Together, these findings highlight sex- and cellular component-dependent changes in protein insolubility as important, modifiable aspects of skeletal muscle proteostasis, and indicate that proteostatic maintenance may be a more important target than anabolism for muscle aging.

physiology↗

bioRxiv2026

Trunk muscle activity across various trunk-limb coordination patterns in centipede locomotion

Animals coordinate movements of their limbs and flexible bodies, yet how trunk muscle activity changes across locomotor patterns remains unclear. We simultaneously recorded electromyograms from trunk muscles (deep dorsal oblique muscles) and trunk-limb kinematics in two centipede species exhibiting retrograde and direct locomotor waves during swimming and walking. During swimming, trunk muscle activity followed a similar phase relationship with trunk bending in both species despite opposite wave directions and different involvement of limbs, suggesting common active generation of undulation. During fast walking, trunk muscle activity was strongest around the ipsilateral swing phase in the undulatory retrograde-wave gait of Scolopendra mutilans, but weaker and associated with the ipsilateral stance phase despite the nearly straight trunk in the direct-wave gait of Scolopocryptops rubiginosus. Together, our findings suggest that the same trunk muscles serve two contrasting mechanical roles depending on locomotor mode: either generating trunk undulation or actively straightening the trunk against limb-induced deformation.

physiology↗

bioRxiv2026

Quantifying and Visualizing the Invisible Hazard of Infant Rebreathing

BACKGROUND: Rebreathing of expired gases during prone infant sleeping contributes to hypoxic and hypercapnic exposure, even without airway obstruction. We investigated how anatomical, physiological, and environmental factors influence aerodynamic rebreathing. METHODS: A dynamically scaled in vitro model simulated prone nasal breathing corresponding to infants weighing 2 to 5 kg, with nostril diameters of 3.2 to 6.0 mm and breathing frequencies of 25 to 40 breaths/min. Ambient temperature and sleep-surface characteristics were varied. Rebreathing was quantified using tracer measurements, while flow visualization revealed the underlying aerodynamic mechanisms. RESULTS: Rebreathing exceeded 60% despite unobstructed nasal openings. Increasing ambient temperature from 23 to 30 degrees C increased rebreathing by 68 to 77%, while reducing simulated infant mass from 5 to 2 kg increased rebreathing by 39 to 46%. Fibrous surfaces increased rebreathing, particularly near inclined nasal openings. A novel finding was that increasing nostril diameter from 3.2 to 6.0 mm increased rebreathing by up to 50%. Flow visualization revealed vortical structures that retained expired fluid near the nasal openings, facilitating re-inspiration. CONCLUSIONS: Aerodynamic rebreathing depends strongly on simulated infant characteristics and sleeping environments. These findings are consistent with established safe-sleep recommendations and identify nostril diameter, for the first time, as a potentially important anatomical factor warranting clinical investigation.

physiology↗