Exercise Training Induces a Hepatic Memory that Synchronizes the Lipid Delivery to Skeletal Muscle

Physiology · 2026-05-01

Endurance exercise is a powerful non-pharmacological strategy to improve metabolic health, but how these benefits persist after training stops remains poorly defined. Emerging studies point to the establishment of a muscle memory of exercise that can enhance muscle growth. The liver is central coordinator of whole-body metabolism, and adaptative responses in exercised muscle depend on effective hepatic metabolic support. Nevertheless, whether an analogous memory exists in the liver has not yet been determined. Here, we tested how endurance training induces a persistent hepatic metabolic memory capable of protecting against the metabolic consequences of an obesogenic diet. Eight-week-old male mice were fed either a control diet (CD; 10% kcal from fat) or a high-fat diet (HFD; 45% kcal from fat) and assigned to sedentary (SED, static cages) or endurance training (voluntary wheel running; VWR). Mice underwent 4-week training (4wk), 4-week detraining (8wk), and 4-week retraining periods (12wk). Timed-exercise CD-fed controls were used to isolate the effects of prior training. Metabolic health, tissue morphology, and transcriptomics were assessed at each time point. In HFD-fed mice, endurance retraining robustly reduced adiposity, significantly improved HOMA-IR, enhanced hepatic gluconeogenic regulation, and suppressed hepatic lipid accumulation. Hepatic transcriptomic analysis revealed that endurance retraining strongly activated hepatic protein and lipid secretory pathways independently from diet. Transcription factor prediction and comparative analysis between endurance retrained and exercise-naïve controls identified the PPARα/RXR–BMAL1/CLOCK/NPAS2 axis as a main pathway associated with the memory. Among the hepatic memory targets, retraining prominently induced carboxylesterase (Ces) gene expression and release, assessed by plasma CES activity, and improved plasma lipid profiles by raising HDL-C and lowering total triglycerides and LDL-C. Using Ldlr-knockout mice, we show that CES proteins directly associate with circulating lipoproteins primarily LDL particles and is inversely correlated with LDL-C levels. Moreover, retraining markedly increased hepatic, plasma, and muscle phosphatidylcholine (PC/LPC) species, which are known circadian lipids that stimulate skeletal muscle fatty acid oxidation. This hepatic PPARα–circadian secretory axis might provide a link for the coordinated response required for the exercise memory that enhances systemic lipid and glucose homeostasis. Our findings point to endurance exercise as an important factor that imprints a hepatic metabolic memory, reactivated upon retraining to protect against diet-induced metabolic dysfunction. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

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2026-03-05

LncRNA-splicing factor condensates regulate hypoxia-responsive pre-mRNA processing near nuclear speckles

Molecular Cell · 2026-03-01 · 2 citations

Zinc-dependent RNA-binding protein controls hepatocyte senescence and recovery from alcohol-related liver failure

Gut · 2026-01-13 · 1 citations

BACKGROUND: Why alcohol-associated liver disease (ALD) resolves after abstinence in most people but progresses to liver failure in others remains poorly understood. Experimental models show that increased exposure to proinflammatory cytokines exacerbates ALD, yet clinical trials targeting these cytokines have failed. The tumour necrosis factor alpha (TNFα)-inducible zinc finger protein 36 (ZFP 36) family of RNA binding proteins controls the outcomes of TNFα exposure by destabilising suites of messenger RNAs (mRNAs) that execute the pleiotropic downstream actions of TNFα. OBJECTIVE: To investigate the role of RNA binding protein ZFP36 ring finger protein like 1 (ZFP36L1) in regulating hepatocyte fate and its contribution to the progression of ALD. DESIGN: We selectively deleted ZFP36L1 in mouse hepatocytes to assess its impact on ALD progression, transcriptional reprogramming, senescence and direct mRNA targets. In parallel, we analysed human liver explants to evaluate ZFP36L1 in relation to hepatocyte senescence, disease severity and zinc-dependent regulation. RESULTS: Deletion of ZFP36L1 exacerbated experimental ALD and activated transcriptional programmes driving ductal transdifferentiation, inflammation and senescence. Mechanistically, ZFP36L1 directly destabilised cyclin-dependent kinase inhibitor 1A (Cdkn1a)(p21) and jagged canonical notch ligand 1 (Jag1) mRNAs, thereby suppressing hepatocyte senescence and JAG1-NOTCH signalling. In human liver explants, ZFP36L1 activity declined in parallel with increasing hepatocyte senescence and ALD severity and was closely associated with impaired zinc-dependent signalling. Manipulation of zinc availability altered ZFP36L1 activity and expression of its direct targets. CONCLUSION: These findings uncover a zinc-dependent ZFP36L1-regulon that governs hepatocyte fate by repressing p21- and JAG1-driven senescence and NOTCH activation and highlight ZFP36L1 as a promising therapeutic target in ALD.

Reducing Cofilin dosage makes embryos resilient to heat stress

bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-03 · 2 citations

Abstract In addition to regulating the actin cytoskeleton, Cofilin also senses and responds to environmental stress. Cofilin can promote cell survival or death depending on context. Yet, many aspects of Cofilin’s role in survival need clarification. Here, we show that exposing early Drosophila embryos to mild heat stress (32°C) induces a Cofilin-mediated Actin Stress Response and upregulation of heat- and ER-stress response genes. However, these responses do not alleviate the negative impacts of heat exposure. Instead, heat stressed embryos show downregulation of hundreds of developmental genes, including determinants of the embryonic body plan, and are less likely to hatch as larvae and adults. Remarkably, reducing Cofilin dosage blunts induction of all stress response pathways, mitigates downregulation of developmental genes, and completely rescues survival. Thus, Cofilin intersects with multiple stress response pathways, and modulates the transcriptomic response to heat stress. Strikingly, Cofilin knockdown emerges as a potent pro-survival manipulation for embryos.

Cancer-associated snaR-A noncoding RNA interacts with core splicing machinery and disrupts processing of mRNA subpopulations

Nature Communications · 2025-11-25

Expansion of RNA polymerase III (Pol III) activity in cancer can activate the transcription of typically silent small RNA genes, including snaR-A (small NF90-associated RNA isoform A), a hominid-specific noncoding RNA that promotes cell proliferation through unclear mechanisms. Here, we show that snaR-A interacts with mRNA splicing factors, including the U2 small nuclear ribonucleoprotein (snRNP) subunit SF3B2, and localizes near subnuclear foci enriched in splicing machinery. Overexpression of snaR-A increases intron retention, a hallmark of inefficient splicing, whereas its depletion enhances splicing of mRNAs characterized by high U2 snRNP occupancy and nuclear speckle proximity. These improvements in splicing coincide with reduced cell proliferation, consistent with tumor-level patterns linking snaR-A to growth in primary cancers. Together, these findings identify snaR-A as a molecular antagonist of splicing and potential disease driver in cancer. We propose that snaR-A-related splicing perturbation may phenocopy splicing defects attributed to U2 snRNP mutations in cancer, eliciting an alternative, non-mutational mechanism of splicing dysregulation during tumorigenesis.

Aberrant Splicing of <i>DNM1L</i> Impairs Cardiac Bioenergetics and Mitochondrial Dynamics in Myotonic Dystrophy Type I (DM1)

Circulation Genomic and Precision Medicine · 2025-11-10

BACKGROUND: Myotonic dystrophy type 1 (DM1) is caused by a (CTG)n trinucleotide repeat expansion in the 3′UTR of the DMPK gene. Once expressed, repeat RNA forms toxic hairpins that sequester the MBNL (muscle blind-like) family of splicing factors. This disrupts the tissue alternative splicing landscape, triggering multisystemic manifestations—myotonia, muscle weakness, cardiac contractile defects, arrhythmia, and neurological disturbances. Although impaired mitochondrial function has been reported in the brain, skeletal muscle, and fibroblasts of patients with DM1, they have not been reported in the heart, nor have their contribution to the DM1 cardiac pathogenesis been explored. Here, we probed the bioenergetic profile of DM1-afflicted heart tissues and explored the mechanistic basis of DM1-induced cardiac bioenergetic defects. METHODS: Using an inducible, heart-specific DM1 mouse model, we performed extracellular flux analyses, measured total ATP and NAD(H) concentrations, and performed immunofluorescence staining and transmission electron microscopy to characterize DM1-induced cardiac bioenergetics and mitochondrial structural defects. We analyzed eCLIP-Seq data to identify mitochondria-related missplicing events, which we validated in human and mouse DM1 heart tissues. Finally, we used antisense oligonucleotides to replicate these events and to test the recapitulation of DM1-like bioenergetic and structural defects in vitro. RESULTS: DM1 induced a multistate decrease in oxygen consumption rate with a corresponding reduction in ATP and NAD(H) concentrations, indicating impaired oxidative phosphorylation in DM1-afflicted mouse hearts. We also found significant cardiac mitochondria fragmentation, which correlated with the missplicing of transcripts encoding mitochondria fission factor ( Mff , encodes MFF protein) and dynamin related protein 1 (Dnm1l, encodes DRP1 protein) in DM1-afflicted human and mouse hearts. Antisense oligonucleotides-mediated redirection of Dnm1l alternative splicing reproduced DM1-like impairment in cardiac bioenergetics and mitochondrial dynamics in wild-type HL-1 cardiomyocytes. CONCLUSIONS: Together, these findings reveal that expanded (CUG)n RNA toxicity in DM1 disrupts cardiac bioenergetics through the missplicing of critical mitochondrial fission transcripts. These misspliced transcripts represent potential therapeutic targets for improving mitochondrial function and cardiac symptoms of DM1.

Dysregulated RNA splicing impairs regeneration in alcohol-associated liver disease

Nature Communications · 2025-09-10 · 4 citations

Individuals with progressive liver failure risk dying without liver transplantation. However, our understanding of why regenerative responses are disrupted in failing livers is limited. Here, we perform multiomic profiling of healthy and diseased human livers using bulk and single-nucleus RNA- and ATAC-seq. We report that in alcohol-associated liver disease, alterations in the hepatic immune milieu prevent hepatocytes from transitioning to proliferative progenitors. We also find differences in RNA binding protein expression, particularly of the ESRP, PTBP, and SR families, leading to misregulation of developmentally controlled RNA splicing. Our data pinpoint ESRP2 as a disease-sensitive splicing factor and support a causal role for its deficiency in the pathogenesis of severe alcoholic hepatitis. Notably, splicing defects in Tcf4 and Slk, two ESPR2 targets, alter their nuclear localization and activities, disrupting WNT and Hippo signaling pathways that are critical for normal liver regeneration. We further demonstrate that changes in stromal cell populations enrich failing livers with TGF-β, which suppresses the ESRP2-driven epithelial splicing program and replaces functional parenchyma with quasi-progenitor-like cells lacking liver-specific functions. Taken together, these findings indicate that misspliced RNAs are effective biomarkers for alcohol-associated liver disease, and targeting them could improve recovery in affected individuals.

Drug delivery agent that acts as a drug for synergistic activity

iScience · 2025-06-13 · 1 citations

results are mixed, the overall results suggest the potential of a new strategy where both drug and delivery agent actively target a disease pathology.

Muscle memory of exercise optimizes mitochondrial metabolism to support skeletal muscle growth

American Journal of Physiology-Cell Physiology · 2025-09-12 · 3 citations

Here we provide evidence that exercise memory in skeletal muscle fine-tunes mitochondrial metabolism to respond to dietary challenges and support muscle growth. Using physiological, RNA sequencing, and biochemical approaches, we show that exercise retraining optimizes mitochondrial metabolism to increase fatty acid oxidative capacity. These findings enhance our understanding of how prior exercise primes muscle for enhanced adaptations, offering insights into strategies to promote healthy aging.