bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.03.12.642752

The denitrosylase SCoR2 controls cardioprotective metabolic reprogramming

Grimmett, Z. W.·Zhang, R.·Zhou, H.-L.·Chen, Q.·Miller, D.·Qian, Z.·Lin, J.·Kalra, R.·Gross, S.·Koch, W. J.·Premont, R. T.·Stamler, J. S.
View original source ↗Export metadata ↓

Abstract

Acute myocardial infarction (MI) is a leading cause of morbidity and mortality, and therapeutic options remain limited. Endogenously generated nitric oxide (NO) is highly cardioprotective, but protection is not replicated by nitroso-vasodilators (e.g., nitrates, nitroprusside) used in clinical practice, highlighting specificity in NO-based signaling and untapped therapeutic potential. Signaling by NO is mediated largely by S-nitrosylation, entailing specific enzymes that form and degrade S-nitrosothiols in proteins (SNO-proteins), termed nitrosylases and denitrosylases, respectively. SNO-CoA Reductase 2 (SCoR2; product of the Akr1a1 gene) is a recently discovered protein denitrosylase. Genetic variants in SCoR2 have been associated with cardiovascular disease, but its function is unknown. Here we show that mice lacking SCoR2/Akr1a1 exhibit robust protection in an animal model of MI. SCoR2 regulates ketolytic energy availability, antioxidant levels and polyol homeostasis via S-nitrosylation of key metabolic effectors. Human cardiomyopathy shows reduced SCoR2 expression and an S-nitrosylation signature of metabolic reprogramming, mirroring SCoR2-/- mice. Deletion of SCoR2 thus coordinately reprograms multiple metabolic pathways--ketone body utilization, glycolysis, pentose phosphate shunt and polyol metabolism--to limit infarct size, establishing SCoR2 as a novel regulator in the injured myocardium and a potential drug target. Impact statementMice lacking the denitrosylase enzyme SCoR2 demonstrate robust cardioprotection resulting from coordinate reprogramming of multiple metabolic pathways. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/642752v2_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@72bfbborg.highwire.dtl.DTLVardef@189cbc4org.highwire.dtl.DTLVardef@1a0cc51org.highwire.dtl.DTLVardef@1c61004_HPS_FORMAT_FIGEXP M_FIG C_FIG

Source connections

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Grimmett, Z. W., Zhang, R., Zhou, H.-L., Chen, Q., Miller, D., Qian, Z., Lin, J., Kalra, R., Gross, S., Koch, W. J., Premont, R. T., Stamler, J. S.. 2025-03-14. The denitrosylase SCoR2 controls cardioprotective metabolic reprogramming. https://doi.org/10.1101/2025.03.12.642752

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

KEEP EXPLORING

Related preprints

bioRxiv2026

Stress-induced Metabolic Remodeling of Adipose and Brain Tissue revealed by Positron Emission Tomography

Stress impacts our health and triggers physiological adaptations, yet the metabolic programs engaged during stress remain incompletely understood. To fill this knowledge gap, we utilized total-body positron emission tomography (PET), multi-OMICS, and endocrine profiling to assess how various murine stress models affect systemic metabolic remodeling. We found that acute immobilization and surgery activate brown adipose tissue as part of the stress response, independently of hypothermia, thereby acting as a highly stress-sensitive metabolic hub. Additionally, we identified stress-specific hypo- and hypermetabolic signatures in different brain regions, and distinguished networks between brain and adipose tissue depots across the different stress groups. Our work presents a novel perspective on stress and its mobilization of metabolic resources and identifies PET imaging of brain and adipose tissue as a valuable, minimally invasive technique for tracking metabolic stress responses in mice, with relevance for animal welfare and disease models, and translational impact for mental health studies and preventive medicine.

physiology↗
bioRxiv2026

Multiparametric in vivo mapping reveals tissue-specific mitochondrial aging trajectories

Mitochondrial dysfunction is a hallmark of aging, yet how mitochondrial states are remodeled across tissues and subcellular compartments in vivo remains elusive. Progress has been limited, in part, because mitochondrial physiology is highly sensitive to experimental perturbations, underscoring the need for minimally disruptive measurement strategies. Here, we establish a tissue-resolved, in vivo framework for the quantitative analysis of mitochondrial states in live, intact Caenorhabditis elegans without confounding effects from mounting-induced hypoxia. This platform couples two-photon fluorescence lifetime imaging microscopy (2p-FLIM) with a custom segmentation pipeline, MitoSLIT, to track functional and structural features across multiple tissues and single neurons. By integrating membrane potential-associated TMRM intensity, lifetime-based microenvironmental metrics, and morphological descriptors, we uncover localized metabolic heterogeneity masked by conventional intensity analysis. Leveraging this framework, we mapped physiological aging against mitochondrial shifts induced by acute stress and fission-fusion mutations. Our analyses reveal that mitochondrial aging is highly tissue-specific, executing distinct trajectories across cell types. Extending the framework to genetically identified neurons revealed age-dependent divergence between somatic and axonal mitochondrial states, accompanied by structural remodeling and a late shift in optical redox ratio. Together, our findings demonstrate that mitochondrial populations do not converge on a uniform bioenergetic endpoint during aging, but rather follow highly compartmentalized, tissue-specific spatiotemporal trajectories in vivo.

physiology↗
bioRxiv2026

Arginine methyltransferase signalling is hyperactive in conditions of neuromuscular junction instability and muscle atrophy

Background: The neuromuscular junction (NMJ) is the site of communication between myofibers and a-motor neurons. Cellular and molecular mechanisms that determine, maintain, and remodel the neuromuscular synapse are poorly understood. Coactivator-associated arginine methyltransferase 1 (CARM1) post-translationally modifies target proteins by methylating arginine residues and has emerged as a key determinant of skeletal muscle biology. Methylarginine signalling is required for the maintenance and repair of the NMJ, but the direct role of CARM1 on the NMJ in health and disease remains unexplored, particularly in humans. Methods: We generated Carm1 skeletal muscle-specific knockout-out (mKO) mice to gain a basic understanding for the role of the enzyme in NMJ biology under homeostatic and denervated conditions. Additionally, we investigated CARM1 activity in severe mouse models of neuromuscular disorders (NMDs) including D2.mdx and Smn2B/- mice, which replicate Duchenne's muscular dystrophy (DMD) and spinal muscular atrophy (SMA), respectively, and exhibit chronic remodelling of the NMJ. Lastly, to evaluate if methylarginine signalling is implicated during NMJ instability in human skeletal muscle, we obtained samples from healthy volunteers before and after 14 days of single leg immobilization as well as from patients with myotonic dystrophy type 1. Results: Our results demonstrated that Carm1 mRNA expression and activity are elevated (P<0.05) in NMJ-enriched regions of healthy murine skeletal muscle. Carm1 muscle-specific deletion reduced NMJ compactness (-9.3%; P<0.05), increased fragmentation (+33%; P<0.05), and disrupted the expression of synapse-specific transcripts basally and following sciatic nerve transection. In skeletal muscle from pre-clinical models of NMDs, we observed a compensatory upregulation in CARM1-dependent arginine methylation as evident by +54% and +71 increases (P<0.05) in asymmetric dimethylarginine (ADMA)-marked CARM1 substrates in DMD and SMA mice, respectively. Similarly, muscle CARM1 was hyperactive with increased NMJ instability during neuromuscular disuse (+22%; P<0.05), and disease (+30%; P<0.05), in humans. In a cohort of muscular dystrophy patients and healthy volunteers, elevated CARM1 signalling was negatively correlated with clinical metrics of skeletal muscle health including grip strength (r = -0.583; P<0.05) as well as positively correlated with mRNA expression of NMJ machinery such as CHRNA1 (r = 0.578; P<0.05). Conclusion: In summary, we highlight that muscle-specific CARM1 is required for maintaining NMJ morphology and transcriptional regulation. Insults to NMJ stability during muscle disuse or in myopathic conditions were associated with enhanced CARM1-mediated methylarginine signalling in mice and humans. Collectively, our findings demonstrate CARM1 as a key mediator of NMJ biology and plasticity in health and disease.

physiology↗