bims-musmir 2026-02-15 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–02–15
27 papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Inhibiting the NLRP3 inflammasome with MCC950 ameliorates muscle atrophy in cancer cachexia.
Sympathetic innervation regulates metabolic flexibility of skeletal muscle.
Single-nuclei RNA-sequencing uncovers sexually divergent exercise signatures partially mimicked by TFEB overexpression in mouse skeletal muscle.
Iron dysregulation and mitochondrial dysfunction in aging: A longitudinal study on mobility decline in low- and high-functioning older adults.
The Vesicular Intersection Layer: A Framework for Cross-Kingdom Extracellular Vesicle Signaling That May Connect Gut Dysbiosis to Skeletal Muscle Wasting in Colorectal Cancer Cachexia.
MicroRNA profiling in post-mortem spinal cord of C9ORF72-related ALS patients reveals molecular pathways involved in motor neuron degeneration.
Mitochondrial double-stranded RNA accumulation in brain aging and Alzheimer's disease.
Tuning tRNA synthetase inhibition reveals parabolic induction of stress granules limited in size and RNA content.
Tributyltin induces conjugation of ATG8s to single membranes via the V-ATPase-ATG16L1 axis, leading to transcription factor EB activation in human cell lines.
Divergent mitochondrial and metabolic adaptations shape selective vulnerability in ALS.
Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia.
The Influence of Acute Beta-Hydroxy Beta-Methylbutyrate (HMB) Ingestion on the Human Skeletal Muscle Transcriptome.
FOSL1 promotes homologous recombination repair and camptothecin resistance via TCOF1-mediated ribosome biogenesis in non-small cell lung cancer.
Single-Nucleus Transcriptome Reveals Cellular Heterogeneity and Transcriptional Response to Heat Stress in Skeletal Muscle.
TRIM25 triggers pyroptosis through mitochondrial DNA release in intestinal ischemia-reperfusion injury.
Altered senescence and mitochondrial transcriptome defines age-related changes in satellite cells.
Inhibition of STING pathway attenuates experimental abdominal aortic aneurysm progression.
Skeletal muscle myosin heavy chain fragmentation following exercise may be linked to post-exercise inflammation and remodelling.
Mitochondria and Lipid Defects in Hereditary Progranulin-Related Frontotemporal Dementia.
Reciprocal regulation between the protein arginine deiminases and mSWI/SNF chromatin remodelers controls skeletal muscle differentiation and regeneration.
The impact of lipid-rich nutrition on ketogenesis and muscle weakness in sepsis.
Golgi fragmentation driven by the USP11-ITCH axis triggers autolysosomal failure in neurodegeneration.
Biological Mechanisms of Strength Preservation During Calorie Restriction-Induced Weight Loss Among Young- to Middle-Aged Adults without Obesity.
A dose-dependent switch in translation capacity controls the transcription factor response to H 2 O 2 stress.
Mitochondrial DNA drives NLRP3-IL-1β axis activation in microglia by binding to NLRP3, leading to neurodegeneration in Parkinson's disease models.
Illuminating Mitochondrial RNA G-Quadruplexes as Structural Brakes on RNA Granule Assembly and OXPHOS.
Mechanical loading induces the longitudinal growth of muscle fibers via a rapamycin-insensitive mechanism.

Eur J Pharmacol. 2026 Feb 10. pii: S0014-2999(26)00136-6. [Epub ahead of print] 178654

Inhibiting the NLRP3 inflammasome with MCC950 ameliorates muscle atrophy in cancer cachexia.

Xiaojuan Pan, Junjie Fu, Xiaofan Gu, Meng Fan, Lixuan Pan, Yun Zhao, Xuan Liu, Xiongwen Zhang.

  Cancer cachexia-associated muscle atrophy represents a critical clinical challenge in advanced malignancies. Cancer cachexia is known as an inflammation-related disease, and the NoD-like receptor family pyrin domain-3 (NLRP3) inflammasome plays a significant role in cancer cachexia, especially in muscle atrophy. In the present study, the efficacy of MCC950, a selective NLRP3 inhibitor, on cancer cachexia-associated muscle atrophy was observed both in cultured C2C12 myotubes underwent various simulated cancer cachexia injuries and in cancer cachexia model mice bearing C26 colon tumor cells. In vitro, MCC950 alleviated C2C12 myotube atrophy induced by conditioned medium from tumor or tumor-macrophage co-cultures. In vivo, MCC950 markedly attenuated cachexia symptoms such as body weight loss and muscle atrophy in C26 tumor-bearing mice. Mechanistically, in tumor or tumor-macrophage co-culture, MCC950 suppresses NLRP3 inflammasome activation, reduces IL-1β and IL-18 release, subsequently decreases the potency of inducing NF-κB activation and Atrogin-1-mediated ubiquitin-proteasome degradation in myotubes, thereby attenuates C2C12 myotube atrophy. Furthermore, in muscle cells, MCC950 directly silences NLRP3 inflammasome signaling, inhibits pyroptosis and IL-1β/IL-18 secretion, suppresses muscle protein degradation to rescue cancer cachexia-driven muscle atrophy. These findings revealed the important role of NLRP3 inflammasome in cancer cachexia and also suggested the possibility of developing NLRP3 inflammasome inhibitors such as MCC950 to be novel therapeutic candidates for cancer cachexia treatment.

Keywords:  Cancer Cachexia; MCC950; Muscle atrophy; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.ejphar.2026.178654
bioRxiv. 2026 Feb 04. pii: 2026.02.02.703364. [Epub ahead of print]

Sympathetic innervation regulates metabolic flexibility of skeletal muscle.

Jordan Owyoung, HaoMin Sima, Junwon Heo, Tess Klugherz, Tina Tian, Brittney Ward, Nikki Boon, Garrett W Cooper, Andrew L Hong, Jarrod Call, Patricia J Ward.

The sympathetic nervous system (SNS) is recognized for its role in the physiological regulation of organs, such as heart, vasculature and lungs, and has emerged as a potential player in skeletal muscle metabolic and neuromuscular junction (NMJ) health. However, the mechanism through which SNS signaling influences skeletal muscle function and adaptation to exercise remains unclear. Using molecular, electrophysiological, immunohistochemical, and high-resolution respirometry techniques, we tested the role of sympathetic innervation to skeletal muscle in response to exercise. Our findings reveal that sympathetic denervation disrupts the NMJ, reducing motor and sympathetic receptor expression, with concomitant deficits in skeletal muscle function. Mechanistically, these deficits are linked to diminished CPT1 enzyme activity, which impairs long-chain fatty acid-mediated oxidation in skeletal muscle mitochondria. These findings reveal a key role for sympathetic innervation in maintaining mitochondrial metabolic function and by extension, skeletal muscle performance, offering novel insight into the interplay between the SNS, exercise, and muscle mitochondria.

DOI: https://doi.org/10.64898/2026.02.02.703364
bioRxiv. 2026 Jan 26. pii: 2026.01.23.700915. [Epub ahead of print]

Single-nuclei RNA-sequencing uncovers sexually divergent exercise signatures partially mimicked by TFEB overexpression in mouse skeletal muscle.

Katrina Granger, Kailin Liu, Tiarra Joseph, Ari Adler, Ian Matthews, Jocelyne Leon, Clayton Baker, Minhoo Kim, Hu Wang, Xianlin Han, Bérénice A Benayoun, Constanza J Cortes.

Exercise induces extensive, cell-type-specific transcriptional remodeling in skeletal muscle to support metabolic flexibility and adaptation. However, the regulatory mechanisms underlying these transcriptional programs, and the extent to which they differ between sexes, remain poorly defined. We previously reported that lifelong, muscle-specific overexpression of human Transcription Factor E-B (cTFEB;HSACre transgenic mice) recapitulates many adaptive features of endurance training in both sexes, leading to profound geroprotective effects during aging even in the absence of exercise. Here, we profile transcriptional adaptations to voluntary wheel running (VWR) and TFEB-overexpression at single-nucleus resolution in young male and female mouse tibialis anterior muscle. This represents, to our knowledge, the first integrated analysis of exercise and TFEB signaling using sex as a biological variable. Using robust bioinformatic and single-nuclei RNA-sequencing approaches, we profiled six muscle-resident cell populations and uncover previously unrecognized, sex-dependent signaling nodes governing exercise-associated metabolic plasticity. TFEB activation and endurance training by VWR elicit strongly correlated transcriptional programs enriched for lipid metabolism, mitochondrial remodeling, and immune modulation, establishing TFEB-overexpression as a partial exercise mimetic. In general, female muscle exhibited enhanced extracellular matrix and lipid-associated responses to endurance training and TFEB overexpression, whereas males preferentially engaged in angiogenic and oxidative networks, revealing distinct sex-specific, sex-dimorphic, or sex-agnostic regulatory routes to metabolic flexibility. Integration with independent multi-omics datasets from endurance-trained rats (MoTrPAC) confirms the conservation of TFEB-exercise transcriptional convergence in skeletal muscle across species and potentially muscle types. Together, these findings define TFEB as a regulator of exercise transcriptional programs and reveal sex-specific molecular frameworks that drive metabolic adaptation in skeletal muscle. Furthermore, the resulting sex-resolved, single-nucleus transcriptional atlas provides a unique resource for the field, enabling comparative, mechanistic, and hypothesis-driven exploration of exercise-responsive skeletal muscle regulatory networks across sexes.

DOI: https://doi.org/10.64898/2026.01.23.700915
Exp Gerontol. 2026 Feb 09. pii: S0531-5565(26)00040-9. [Epub ahead of print] 113062

Iron dysregulation and mitochondrial dysfunction in aging: A longitudinal study on mobility decline in low- and high-functioning older adults.

Nevena Stanojevic, Stephanie Wohlgemuth, Rola S Zeidan, XiangYang Lou, Javier A Tamargo, Bella Bravo, Jennifer Newman, Anna Picca, Emanuele Marzetti, Kevin Wu, Christian McLaren, Robert Mankowski, Bhanuprasad Sandesara, Aditya Shirali, Todd Manini, Christiaan Leeuwenburgh, Stephen Anton.

   BACKGROUND: Mobility loss in older adults reduces quality of life and increases risks of falls, hospitalizations, and mortality. Low-functioning (LF) older adults experience faster mobility decline than their high-functioning (HF) peers, but the underlying biological mechanisms remain unclear. Although iron accumulation in aging muscle mitochondria has recently been linked to lower physical function, its longitudinal impact on physical function remains understudied.
METHODS: Muscle Iron Flow is a prospective, observational study which enrolled LF and HF older adults (N = 114; age 75.8 ± 3.2 years, 64.9% female) to examine links between iron dysregulation, mitochondrial function, and physical performance. Assessments include blood biomarkers, physical function tests, and behavioral measures (diet, activity, sleep, medication use), collected at baseline and annually, and muscle biopsies obtained at baseline and year three. This manuscript reports baseline characteristics and measurement procedures only; longitudinal portion is ongoing.
RESULTS: At baseline, HF older adults demonstrated significantly better physical performance than LF adults across all functional tests, including Short Physical Performance Battery (SPPB), 6-minute walk distance, handgrip strength, and knee extensor torque (ps < 0.05). LF participants also had lower hemoglobin levels and higher red cell distribution width (RDW; ps < 0.05).
DISCUSSION: This study is among the first to investigate how biomarkers of iron dysregulation, mitochondrial function, and related ferroptosis and senescence pathways may contribute to changes in physical function in LF and HF older adults. By integrating molecular and functional assessments, the study will inform how disrupted iron handling and mitochondrial health influence mobility trajectories in aging populations.

Keywords:  Aging; Ferritin; Inflammation; Mitochondrial dysfunction; Muscle strength; Physical function; iron regulation

DOI:  https://doi.org/10.1016/j.exger.2026.113062
Cancers (Basel). 2026 Feb 05. pii: 522. [Epub ahead of print]18(3):

The Vesicular Intersection Layer: A Framework for Cross-Kingdom Extracellular Vesicle Signaling That May Connect Gut Dysbiosis to Skeletal Muscle Wasting in Colorectal Cancer Cachexia.

Young-Sool Hah, Seung-Jun Lee, Jeongyun Hwang, Seung-Jin Kwag.

  Colorectal cancer (CRC) cachexia is a multifactorial, treatment-limiting syndrome characterized by progressive loss of skeletal muscle with or without loss of fat mass, accompanied by systemic inflammation, anorexia, metabolic dysregulation, and impaired treatment tolerance. Despite decades of work, cachexia remains clinically underdiagnosed and therapeutically underserved, in part because canonical models treat tumor-derived factors and host inflammatory mediators as a largely 'host-only' network. In parallel, CRC is strongly linked to intestinal dysbiosis, barrier disruption, and microbial translocation. Extracellular vesicles (EVs)-host small EVs, tumor-derived EVs, and bacterial extracellular vesicles (including outer membrane vesicles)-may provide a mechanistically plausible, information-dense route by which these domains could be coupled. Here, we synthesize emerging evidence suggesting that cross-kingdom EV signaling may operate as a vesicular ecosystem spanning gut lumen, mucosa, circulation, and peripheral organs. We propose the "vesicular intersection layer" as a unifying framework for how heterogeneous EV cargos converge on shared host decoding hubs (e.g., pattern-recognition receptors and stress-response pathways) to potentially contribute to muscle catabolism. We critically evaluate what is known-and what remains unproven-about EV biogenesis, trafficking, and causal mechanisms in CRC cachexia, highlight methodological constraints in microbial EV isolation and attribution, and outline minimum evidentiary standards for cross-kingdom claims. Finally, we translate the framework into actionable hypotheses for EV-informed endotyping, biomarker development (including stool EV assays), and therapeutic strategies targeting shared signaling nodes (e.g., TLR4-p38) and endocrine mediators that are predominantly soluble but may be fractionally vesicle-associated (e.g., GDF15). By reframing CRC cachexia as an emergent property of tumor-host-microbiota vesicular communication, this review provides a roadmap for mechanistic studies and clinically tractable interventions.

Keywords:  GDF15; TLR4; bacterial extracellular vesicles; biomarkers; cachexia; colorectal cancer; endotypes; extracellular vesicles; gut microbiome; skeletal muscle wasting

DOI:  https://doi.org/10.3390/cancers18030522
Front Neurosci. 2026 ;20 1741065

MicroRNA profiling in post-mortem spinal cord of C9ORF72-related ALS patients reveals molecular pathways involved in motor neuron degeneration.

Giorgia Farinazzo, Eleonora Giagnorio, Matteo Marcuzzo, Marco Cattaneo, Claudia Malacarne, Paola Cavalcante, Silvia Bonanno, Emanuela Maderna, Viviana Pensato, Cinzia Gellera, Gianluca Marucci, Samanta Mazzetti, Erika Salvi, Giuseppe Lauria, Stefania Marcuzzo.

   Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder causing progressive motor neuron death in cortex, brainstem and spinal cord. The most common genetic cause is the G4C2 hexanucleotide repeat expansion in the non-coding region of exon 1 of C9ORF72, accounting for ~40% of familial and ~7% of sporadic ALS. RNA dysregulation is increasingly recognized as a key contributor to ALS pathogenesis. This study aimed to identify specific microRNAs (miRNAs) involved in motor neuron degeneration in C9ORF72-ALS.
Methods: We profiled 754 miRNAs in human post-mortem spinal cord tissue from C9ORF72-ALS patients and healthy donors. Laser capture microdissection isolated ventral horn regions, and in silico target prediction identified potential genes and pathways regulated by differentially expressed miRNAs. Target genes were validated by Real time PCR.
Results: Two subsets of miRNAs were exclusively expressed in ventral horn regions: miR-200b-3p and miR-346 in C9ORF72-ALS patients, and miR-30d-5p, miR-106b-5p and miR-135a-5p in healthy donors. Target prediction and molecular analysis identified putative genes and pathways linked to cell death, inflammation, protein metabolism, DNA modification, excitotoxicity, autophagy and vesicles trafficking.
Discussion: This study identifies specific miRNAs and their target genes as key molecules in motor neuron degeneration in C9ORF72-ALS. Restoring their expression could represent a therapeutic approach for ALS.

Keywords:  C9ORF72-amyotrophic lateral sclerosis; human post-mortem spinal cord tissue; microRNAs; motor neuron; target genes

DOI:  https://doi.org/10.3389/fnins.2026.1741065
bioRxiv. 2026 Feb 04. pii: 2026.02.02.703345. [Epub ahead of print]

Mitochondrial double-stranded RNA accumulation in brain aging and Alzheimer's disease.

Rachel L Doser, Thomas J LaRocca.

Mitochondria and inflammation are tightly linked in aging and Alzheimer's disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using human brain tissue and complementary in vitro transcriptomic datasets, quantifying mitochondrial transcripts and dsRNA editing. We found that mt-dsRNA accumulated after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt-dsRNA-driven inflammation. In AD brains, mt-dsRNA accumulation was further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration by identifying mt-dsRNA as a potential driver of chronic inflammation.
Abstract Figure:

DOI: https://doi.org/10.64898/2026.02.02.703345
RNA. 2026 Feb 08. pii: rna.080883.125. [Epub ahead of print]

Tuning tRNA synthetase inhibition reveals parabolic induction of stress granules limited in size and RNA content.

Max Baymiller, Noah S Helton, Benjamin Dodd, Stephanie L Moon.

  Translation elongation defects cause ribosome stalling and activate the integrated stress response (ISR). During the ISR, translation initiation suppression and ribosome runoff drive mRNA condensation into stress granules. However, the effects of partial translation elongation inhibition on stress granules are poorly defined. We demonstrate that intermediate levels of tRNA synthetase inhibitors activate the ISR and cause assembly of stress granules in a parabolic dose-response pattern. These stress granules are limited in size and number due to ribosome association with mRNAs. Assembly of stress granules by intermediate levels of the prolyl-tRNA synthetase inhibitor halofuginone requires the canonical stress granule scaffolding proteins G3BP1/2 and GCN2-mediated ISR activation. We performed a candidate-based comparative analysis of the composition of stress granules induced by intermediate levels of halofuginone or canonical stressors arsenite or thapsigargin. The stress granules induced by halofuginone, arsenite, or thapsigargin harbor polyadenylated RNA and the canonical stress granule proteins PABPC1, G3BP1, and UBAP2L. We observe stress- and transcript- specific differences in the localization of candidate RNA molecules to stress granules. These results demonstrate that partial translation elongation inhibition permits stress granule assembly through the balance of ISR activation and mRNA association with ribosomes, with implications for the stress response associated with amino acid or tRNA deficiency, therapeutic tRNA synthetase inhibition, or diseases associated with tRNA synthetase mutations.

Keywords:  integrated stress response; stress granules; tRNA synthetase; translation; translation elongation

DOI:  https://doi.org/10.1261/rna.080883.125
Arch Toxicol. 2026 Feb 07.

Tributyltin induces conjugation of ATG8s to single membranes via the V-ATPase-ATG16L1 axis, leading to transcription factor EB activation in human cell lines.

Shunichi Hatamiya, Masatsugu Miyara, Nanako Takahashi, Ami Oguro, Yaichiro Kotake.

  Tributyltin (TBT) is an environmental contaminant that induces diverse toxic effects in mammals, but the cellular mechanisms underlying adaptation to TBT stress remain poorly understood. Conjugation of ATG8s to single membranes (CASM) is a noncanonical LC3‑lipidation pathway activated by various stressors, distinct from canonical autophagy. We previously showed that TBT reduces lysosomal acidity and inhibits autophagy in SH-SY5Y cells. Furthermore, we observed TBT-induced LC3-II accumulation, which was reduced by bafilomycin A1, and tubular LC3-positive structures as hallmarks of CASM. In this study, we investigated whether TBT activates CASM. TBT (700 nM) induced LC3-II accumulation, which was completely blocked by bafilomycin A1 in SH-SY5Y and HeLa cells. Unlike autophagy, TBT induced LC3-II accumulation even under class III PI3K inhibition by wortmannin and in FIP200-knockout cells. Salmonella effector protein SopF, which inhibits V-ATPase-ATG16L1 association required for CASM, inhibited TBT-induced LC3-II accumulation. In FIP200-knockout cells, TBT induced LC3 accumulation on lysosomes, the primary CASM target. TBT also promoted nuclear translocation of transcription factor EB (TFEB) in a SopF-sensitive manner. Together, these results identify CASM as a lysosomal stress response to TBT, induced via the V-ATPase-ATG16L1 axis, leading to TFEB activation. This mechanism provides a toxicological framework for understanding xenobiotic-induced lysosomal adaptations.

Keywords:  CASM; LC3; Lysosome; Noncanonical autophagy; TFEB; Tributyltin

DOI:  https://doi.org/10.1007/s00204-026-04300-7
bioRxiv. 2026 Feb 02. pii: 2026.01.30.702552. [Epub ahead of print]

Divergent mitochondrial and metabolic adaptations shape selective vulnerability in ALS.

Bianca A Cotto, Lizi Zhang, Benjamin Fait, Chris Peralta, Ece Kilic, Henrik Molina, Nathaniel Heintz, Eric F Schmidt.

Neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) exhibit striking cell-type selectivity, yet the basis for this vulnerability remains elusive. Here, we uncover that even closely related neurons can harbor distinct mitochondrial properties that shape their response to disease. Using TOM-Tag, a circuit-based AAV-based strategy for cell type-specific mitochondrial immunopurification from projection neurons, we performed integrative proteomic, metabolomic, transcriptomic, and functional analyses of mitochondria from ALS-vulnerable corticospinal projection neurons (CSPNs) and resilient corticothalamic projection neurons (CTPNs) in vivo. We discovered that CSPNs and CTPNs exhibit divergent mitochondrial profiles at baseline, despite sharing cortical layer and developmental origin. CTPNs were primed for antioxidant buffering and fatty acid metabolism, whereas CSPNs were enriched for oxidative phosphorylation components. In ALS, CTPNs employed mitochondrial flexibility and redox defense, whereas CSPNs exhibited respiratory failure and metabolic stress. These findings reveal that intrinsic mitochondrial programs vary even between similar neurons, and that this hidden layer of diversity may critically shape susceptibility to neurodegeneration. By enabling high-resolution access to mitochondria in defined neuronal circuits, TOM-Tag offers a powerful new lens for dissecting disease mechanisms and identifying cell-specific therapeutic targets.

DOI: https://doi.org/10.64898/2026.01.30.702552
Cancer Cell. 2026 Feb 12. pii: S1535-6108(26)00053-X. [Epub ahead of print]

Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia.

Xiuhui Shi, Alex X Arreola, Zhijun Zhou, Jingxuan Yang, Mingyang Liu, Yang Cai, Yu Ren, Hao Yuan, Qun Chen, Xinjie Chen, Xinyu Yang, Yimei Meng, Jingyi Wang, Wenyi Luo, Michael C Rudolph, Rohan Varshney, Kar-Ming Fung, Chao Xu, Wei R Chen, Michael S Bronze, Lei Zheng, Yi-Ping Li, Courtney W Houchen, Yuqing Zhang, Min Li.

  Cancer-induced cachexia and anorexia are debilitating complications across many cancers, yet effective treatments remain limited due to a poor understanding of the underlying mechanisms. Here, we identify an uncharacterized tumor-immune-neural circuit driving these syndromes, centered on growth and differentiation factor 15 (GDF15). Using genetically engineered mouse models, we find that loss of GDF15 protects against appetite loss, muscle wasting, and fat loss in pancreatic, lung, and skin cancers. Single-cell RNA sequencing reveals macrophages as a major source of GDF15, induced by tumor-derived colony-stimulating factor 1 (CSF1). GDF15 acts via the central nervous system to enhance β-adrenergic signaling in the tumor microenvironment, thereby amplifying cachexia. The disruption of this feedforward loop with GDF15-neutralizing antibody, anti-CSF1R antibody, or Rearranged during Transfection (RET) inhibitor markedly reduces both cachexia and anorexia. These findings reveal a non-cell-autonomous mechanism linking tumor signals, macrophage-derived GDF15, and neural pathways, highlighting the tumor-immune-neural triad as a promising therapeutic target.

Keywords:  adipose loss; body composition; energy expenditure; hormone; metabolic stress; muscle atrophy; norepinephrine; sympathetic nerve; tumor immune microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.ccell.2026.01.014
Nutrients. 2026 Jan 28. pii: 434. [Epub ahead of print]18(3):

The Influence of Acute Beta-Hydroxy Beta-Methylbutyrate (HMB) Ingestion on the Human Skeletal Muscle Transcriptome.

Daniel J Wilkinson, Iain J Gallagher, Hannah Crossland, Suzette L Pereira, Ricardo Rueda, Bethan E Phillips, Kenneth Smith, Colleen S Deane, Philip J Atherton.

  Background: Nutritional interventions to mitigate age/disease-related skeletal muscle attrition are much needed given the growing older population. Beta-hydroxy beta-methylbutyrate (HMB), an endogenous metabolite of the essential amino acid leucine, has anabolic properties in skeletal muscle: acutely stimulating muscle protein synthesis and attenuating muscle protein breakdown. While the role of supplemental HMB on muscle protein turnover is established, mechanistic effects on the muscle transcriptome have not been examined. Methods: Total RNA was extracted from m. vastus lateralis muscle biopsies of young males (n = 14) before and ~2.5 h after oral consumption of ~3 g HMB. Global changes in the muscle transcriptome were assessed via RNA sequencing, and differential expression in genes between fasted and 'fed' (HMB) conditions was determined. To identify the functional biology of differentially expressed genes, gene set enrichment and active subnetwork-orientated enrichment analyses was performed. Results: Of 15,982 genes detected, 468 were significantly upregulated and 326 were significantly downregulated in response to HMB. These genes were found to be associated with molecular pathways regulating muscle protein turnover, most notably, JAK-STAT signalling (e.g., STAM), circadian rhythm (e.g., NR1D1, NR1D2, PER2, PER3), TNFα signalling (e.g., TNFRSF1A, CCL2, CXCL2), and protein synthesis (e.g., POLR1A, POLR2A, POLR3A, PIK3RR, SGK1). HMB also regulated the expression of AA transporters, evoking a robust increase in SLC36A1 (PAT1) and SLC7A5 (LAT1). Conclusions: HMB evokes transcriptional events important in the homeostasis of muscle, supporting a role in proteostasis and one akin to protein intake, i.e., upregulation of AA transporters. Future work should further define HMB's transcriptomic/proteomic effects in ageing/disease and synergy with exercise.

Keywords:  RNA sequencing; amino acid transporters; beta-hydroxy beta-methylbutyrate (HMB); circadian rhythm; inflammation; skeletal muscle; transcriptome

DOI:  https://doi.org/10.3390/nu18030434
Transl Oncol. 2026 Feb 12. pii: S1936-5233(26)00038-0. [Epub ahead of print]66 102701

FOSL1 promotes homologous recombination repair and camptothecin resistance via TCOF1-mediated ribosome biogenesis in non-small cell lung cancer.

Chunmei Hao, Luojun Chen, Fuben Liao, Lulu Chen, Yi Yao, Qibin Song.

   BACKGROUND: Camptothecin (CPT) and its derivatives are important chemotherapeutic agents; however, intrinsic and acquired tolerance frequently limits their long-term efficacy. This study aimed to identify key transcriptional regulators of CPT responsiveness in non-small cell lung cancer (NSCLC) and to elucidate the underlying molecular mechanisms.
METHODS: Single-cell RNA sequencing-based transcriptomic profiling, integrated with bulk RNA-seq, was used to prioritize CPT-responsive transcriptional programs and nominate candidate regulators. Functional roles were validated using gain- and loss-of-function approaches in NSCLC cell lines. DNA damage repair, ribosome biogenesis, and translational activity were assessed using molecular and reporter assays. Pharmacological inhibition of ribosome biogenesis was evaluated using the RNA polymerase I inhibitor BMH-21, and therapeutic relevance was further examined in xenograft models.
RESULTS: We identified FOSL1 as a CPT-responsive transcription factor that was associated with poor prognosis in lung adenocarcinoma. CPT treatment induced FOSL1 expression and nuclear accumulation, whereas FOSL1 depletion markedly enhanced CPT-induced cytotoxicity. Mechanistically, loss of FOSL1 resulted in persistent DNA damage accumulation and selective impairment of homologous recombination (HR) repair. FOSL1 sustained HR repair indirectly by promoting ribosome biogenesis through transcriptional activation of TCOF1. Pharmacological inhibition of ribosome biogenesis phenocopied FOSL1 depletion and significantly potentiated CPT efficacy both in vitro and in vivo.
CONCLUSION: Our study defines a FOSL1-TCOF1-ribosome axis that promotes CPT tolerance in NSCLC by maintaining HR repair. These findings provide a rationale for targeting ribosome biogenesis to enhance CPT-based treatment and highlight coordinated regulation of transcription, protein synthesis, and DNA repair under chemotherapeutic stress.

Keywords:  Camptothecin resistance; FOSL1; Homologous recombination; Ribosome biogenesis

DOI:  https://doi.org/10.1016/j.tranon.2026.102701
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70217

Single-Nucleus Transcriptome Reveals Cellular Heterogeneity and Transcriptional Response to Heat Stress in Skeletal Muscle.

Ziyin Han, Li Chen, Zhiyu Lei, Jiaman Zhang, Ziyu Chen, Xiaolan Fan, Bo Zeng, Anan Jiang, Hai Xiang, Hua Li, Mingzhou Li, Long Jin.

   BACKGROUND: Heat stress can induce skeletal muscle injury. Typical characteristics of heat-exposed muscle tissues include apoptosis, oxidative stress and autophagy. The understanding of molecular mechanisms underlying heat stress-induced muscle injury is limited, especially at the single-cell transcription level.
METHODS: We collected skeletal muscles from 12-week-old female C57BL/6J mice in control (NC) and four heat stress groups. The experimental scheme comprised five groups: NC (25.5°C ± 0.5°C), HS0 (after ~3-h heat exposure, 41.5°C ± 0.5°C), HS8, HS16 and HS24 group (recovery at 25.5°C ± 0.5°C for 8, 16 and 24 h, respectively). Skeletal muscles were subjected to HE staining (n = 6), TUNEL staining (n = 3) and transmission electron microscopy (n = 3). Transcripts were measured at the tissue (n = 5 or 6) and single-nucleus levels (n = 2).
RESULTS: Histologically, myofibrillar structure deformation, mitochondrial swelling and fusion, intramuscular triglyceride accumulation and autophagy occurred in the muscles subjected to heat stress. At the tissue level, a gene cluster associated with the response to heat exhibited an increasing trend of transcription in the HS0 versus NC groups, and the levels decreased to those in the NC group after 16 h. At the single-cell level, 134 320 high-quality myonuclei were collected from the muscles and annotated as seven cell types, including myonuclei, muscle stem cells (MuSCs) and immune cells. We identified the larger number of differentially expressed genes in the myonuclei. After heat stress, new cell clusters appeared in type IIa/IIx (HS8 group) and IIb (HS0 group) myonuclei but not in type I myonuclei. Generally, immediate early genes, highly expressed genes and transcription factor regulons identified in new cell clusters induced by heat were related to responses to heat, heat shock, oxidative stress and antioxidative stress. To repair the injured muscles, MuSCs highly expressed the development-related genes, such as Atp2a1, Ckm, Myh1, Aldoa, Pde4d and Pdlim5. Analysis of cell-cell communication showed that Dag1 and Egf signals associated with myonuclei were the underlying pathways that participated in repair tissues.
CONCLUSIONS: We constructed the largest transcriptomic dataset, to date, for heat-exposed skeletal muscles. At tissue resolution, the response of muscles to heat stress was eliminated after a recovery period of 16 h. At single-nucleus resolution, the myofibre was the most heat-sensitive cell type, and type IIb myonuclei were the most heat-sensitive subtype of myonuclei. To our knowledge, this is the first study to reveal the molecular mechanisms underlying heat-induced muscle injury and repair at the single-cell transcriptional level.

Keywords:  bulk RNA‐seq; cell–cell communication; heat stress; muscle stem cells; myonuclei; snRNA‐seq

DOI:  https://doi.org/10.1002/jcsm.70217
Free Radic Biol Med. 2026 Feb 10. pii: S0891-5849(26)00116-4. [Epub ahead of print]

TRIM25 triggers pyroptosis through mitochondrial DNA release in intestinal ischemia-reperfusion injury.

Song Yao, Xiaolong Lu, Ximeng Ren, Meng Li, Fanrui Meng, Yuxin Miao, Dapeng Ding, Yang Liu.

  Ischemia-reperfusion injury refers to the damage that occurs in an organ or tissue following the restoration of blood supply after a period of ischemia. Intestinal ischemia-reperfusion injury (I/R) represents a worldwide public health issue characterized by excessive inflammation and currently lacks effective clinical therapies. Activation of the NLRP3 inflammasome is not only a hallmark feature of intestinal I/R but also serves as a significant exacerbating factor in intestinal deterioration. TRIM25 is involved in regulating endoplasmic reticulum stress, the unfolded protein response, and inflammatory responses. However, its specific role in intestinal I/R remains unclear and may be associated with the activation of the NLRP3 inflammasome. In the intestinal tissues of mice subjected to intestinal I/R, TRIM25 expression was significantly upregulated and showed a positive correlation with NLRP3 inflammasome activation. Knockdown of TRIM25 suppressed hypoxia-reoxygenation (H/R)-induced activation of the NLRP3 inflammasome and the cGAS-STING pathway. It also reduced mitochondrial reactive oxygen species production, alterations in mitochondrial membrane potential, and cytosolic release of mitochondrial DNA. Moreover, NLRP3 inflammasome activation during intestinal I/R was attenuated by both cGAS knockdown and treatment with a specific cGAS inhibitor. Mechanistically, TRIM25 interacts with and potentially ubiquitinates the mitochondrial outer membrane phosphatase PGAM5, which leads to increased mitochondrial membrane permeability and thereby promotes the leakage of mtDNA into the cytosol. The leaked mtDNA is subsequently recognized by cGAS, initiating the activation of its downstream coupled STING pathway-a key component of the innate immune system responsible for detecting the presence of cytosolic DNA. Consequently, our results demonstrate that TRIM25-mediated mtDNA release, induced through its direct interaction with PGAM5, which in turn leads to the activation of the cGAS-STING pathway. This activation represents a critical determinant of NLRP3 inflammasome activation and intestinal injury. Accordingly, therapeutic targeting of this signaling pathway may hold potential for the treatment of intestinal I/R.

Keywords:  Intestinal ischemia-reperfusion injury (I/R); Pyroptosis; cGAS-STING pathway; mtDNA

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.02.019
Front Cell Dev Biol. 2025 ;13 1699206

Altered senescence and mitochondrial transcriptome defines age-related changes in satellite cells.

Fasih A Rahman, Joe Quadrilatero.

  Aging impairs the regenerative capacity of skeletal muscle in part through the functional decline of the resident stem cell population called satellite cells. With age, satellite cells exhibit a loss of quiescence, altered proliferation, and impaired differentiation, leading to incomplete myogenesis following injury. Mitochondria are central to stem cell function, providing ATP, regulating redox homeostasis, and integrating several signaling pathways during lineage progression. While mitochondrial remodeling and function is essential for supporting the metabolic demands of myogenesis, the extent to which these processes are altered in aged satellite cells across cell states remains unclear. To address this, we performed a comparative transcriptomic analysis of young and aged satellite cells in quiescent, proliferating, and early differentiating states using three publicly available microarray datasets. Our results reveal that aged satellite cells exhibit a dysregulated senescence profile, characterized by the simultaneous upregulation of both senescence-inducing and -inhibiting genes, suggestive of a metastable senescence state. These features persisted during early differentiation, where aged cells also displayed increased expression of senescence-associated secretory phenotype (SASP) components, potentially contributing to a pro-inflammatory niche. Mitochondrial gene expression was relatively stable in quiescent cells but showed marked remodeling upon activation, particularly in aged cells. While young satellite cells upregulated transcriptional programs related to mitochondrial function, aged cells exhibited broader and less coordinated responses enriched for stress, apoptotic, and metabolic pathways. Despite evidence of mitochondrial stress, mitophagy gene activation remained limited in aged cells, raising the possibility of impaired organelle quality control. Together, our findings highlight age-associated disruptions in both senescence and mitochondrial remodeling programs across the satellite cell lifecycle. These transcriptional changes likely underlie impaired regenerative responses in aging muscle and identify potential targets for rejuvenating muscle stem cell function.

Keywords:  SASP; aging; mitochondrial remodeling; satellite cell; senescence; skeletal muscle; skeletal muscle regeneration

DOI:  https://doi.org/10.3389/fcell.2025.1699206
Acta Pharmacol Sin. 2026 Feb 10.

Inhibition of STING pathway attenuates experimental abdominal aortic aneurysm progression.

Yu-Xin Chen, Chen-Rui Shen, Fang-Fang Xu, Chen-Jun Han, Yu-Jie Xi, Yu Shi, Yu-Ping Xu, Dong-Jie Li, Jian Zhou, Fu-Ming Shen, Hui Fu.

  Abdominal aortic aneurysm (AAA) is a chronic, inflammatory and degenerative vascular disease. Previous studies have demonstrated that stimulator of interferon genes (STING) is involved in multiple inflammatory diseases. However, the role of STING in AAA formation and its possible mechanisms have yet to be investigated. Here, we investigated the role of STING in the development of AAA using two murine AAA models induced by porcine pancreatic elastase (PPE)/β-aminopropionitrile (BAPN) or angiotensin II (Ang II). The STING signaling pathway was significantly activated in AAA tissues from both mice and patients. Sting mutation slowed AAA formation, as confirmed by reduced AAA incidence, maximal abdominal aortic diameter, elastin disruption, collagen deposition, and inhibited immune cell infiltration in AAA mice. RNA-sequencing analysis revealed that compared with the control, Sting mutation inhibited inflammatory and immune responses in AAA tissues. Similar effects were observed after pharmacological inhibition of STING in Ang II infused ApoE-/- mice. Besides, STING signaling pathway was also activated in TNFα treated MOVAS. Sting knockdown suppressed inflammatory response and oxidative stress in vitro. Finally, colchicine protected against AAA formation in mice partially through inhibition of the STING signaling pathway. Our study demonstrated that Sting mutation and pharmacological inhibition could limit AAA progression possibly through inhibition of inflammation and oxidative stress. Colchicine could slow AAA formation in a partially STING-dependent manner in AAA mice. These findings suggest that STING might be a potential pharmacological target for the treatment of AAA.

Keywords:  STING; abdominal aortic aneurysm; colchicine; inflammation; oxidative stress

DOI:  https://doi.org/10.1038/s41401-026-01758-0
Exp Physiol. 2026 Feb 11.

Skeletal muscle myosin heavy chain fragmentation following exercise may be linked to post-exercise inflammation and remodelling.

Dakota R Tiede, Diego Bittencourt, J Max Michel, Daniel L Plotkin, Madison L Mattingly, Derick A Anglin, Christopher G Vann, Zachary A Graham, Timothy J Broderick, Marcas M Bamman, Michael D Roberts.

  The purpose of this exploratory investigation was to determine if acute post-exercise skeletal muscle myosin heavy chain fragmentation (MyHCfrag) coincides with alterations in molecular chaperones and proteolytic enzymes, select markers of mammalian target of rapamycin complex 1 (mTORC1) signalling, and/or specific gene expression signatures. Untrained males (n = 10, 23 ± 2 years) and females (n = 10, 23 ± 3 years) completed a bout of combined endurance and resistance exercise. Vastus lateralis muscle biopsies were taken before, 3 h and 24 h post-exercise. Tissue was fractioned into myofibrillar (MF) and sarcoplasmic protein (SF) fractions for protein analysis. Differential RNA expression (DE) from those who experienced high and low MyHCfrag post-exercise was also analysed via bulk RNA-sequencing. MyHCfrag increased 24 h post-exercise, albeit only four of 20 chaperone and proteolytic markers were concomitantly altered and none significantly correlated with 24 h post-exercise MyHCfrag. Given these null findings, we explored six participants who experienced the most post-exercise MyHCfrag versus six who experienced the least MyHCfrag with the intent of examining if post-exercise gene signatures or signalling differed. Although mTORC1 signalling markers were similar, 799 DE transcripts were identified 24 h post-exercise. Pathway analysis on DE differences indicated that nine of the top 10 pathways enriched in high-MyHCfrag participants were related to inflammation. High MyHCfrag participants also presented an upregulation in extracellular matrix remodelling genes at the 24 h post-exercise time point. Though we lack immunohistochemical data, these findings suggest that post-exercise MyHCfrag is associated with an upregulation in an inflammatory and remodelling signature, and longer-term studies are needed to determine if these acute outcomes align with unique adaptive responses.

Keywords:  fragmentation; inflammation; myosin heavy chain; resistance training

DOI:  https://doi.org/10.1113/EP093340
Cells. 2026 Feb 01. pii: 276. [Epub ahead of print]15(3):

Mitochondria and Lipid Defects in Hereditary Progranulin-Related Frontotemporal Dementia.

Jon Ondaro, Jose Luis Zúñiga-Elizari, Mónica Zufiría, Maddi Garciandia-Arcelus, Ángela Sánchez Molleda, Miren Zulaica, Miguel Lafarga, Javier Riancho, Adolfo López de Munaín, Fermin Moreno, Francisco Javier Gil-Bea, Gorka Gerenu.

  Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting individuals under 65 years of age, characterized by significant behavioral and language disabilities. Despite extensive research efforts, effective treatments for FTD remain elusive. Familial cases of FTD have been linked to genetic mutations in several key genes, among these, mutations in granulin (GRN) account for 5-20% of cases, leading to haploinsufficiency of progranulin (PGRN), a multifunctional glycoprotein. This study investigates the cellular pathology associated with GRN insufficiency by using fibroblasts derived from FTD patients carrying the c.709-1G>A GRN mutation (FTD-GRN). These fibroblasts exhibited pathological hallmarks of FTD, including lysosomes, autophagosomes, and lipofuscin accumulation, mirroring observations in affected patient tissues. Notably, we report mitochondrial abnormalities, characterized by mitochondrial swelling which is associated with decreased mitochondrial respiration, and lipid droplet accumulation, reflecting altered lipid metabolism. Experimental supplementation with recombinant human progranulin (rhPGRN) was associated with recovery of lysosomal acidification and attenuation of mitochondrial and lipid abnormalities in vitro. This study reveals that GRN haploinsufficiency induces mitochondrial and lipid dysfunctions, suggesting that these pathways may contribute to FTD-GRN pathogenesis and could be of interest for therapeutic development.

Keywords:  FTD; GRN; frontotemporal dementia; lipid droplets; lysosome; mitochondria; neurodegeneration; progranulin

DOI:  https://doi.org/10.3390/cells15030276
bioRxiv. 2026 Jan 21. pii: 2026.01.20.700682. [Epub ahead of print]

Reciprocal regulation between the protein arginine deiminases and mSWI/SNF chromatin remodelers controls skeletal muscle differentiation and regeneration.

Monserrat Olea-Flores, Tapan Sharma, Anand Parikh, Leonard Barasa, Sarah Hachmer, F Jeffrey Dilworth, Teresita Padilla-Benavides, Paul R Thompson, Anthony N Imbalzano.

Protein arginine deiminases (PADs) post-translationally convert arginine to citrulline on target proteins and serve as regulators of multiple cellular functions. PAD enzymes have been implicated in autoimmune disorders, cancer, and other diseases. Inhibiting PAD activity is currently being pursued clinically for therapeutic purposes. However, little is known about PAD function in normal developmental or homeostatic processes. Here we show that multiple PAD isoforms contribute to primary myoblast differentiation by binding to regulatory regions of target genes. Furthermore, we demonstrate a novel, reciprocal requirement for PADs and mammalian SWI/SNF (mSWI/SNF) chromatin remodeling enzymes; PAD enzymes are required for the expression and binding of specific mSWI/SNF enzyme subunits to target gene regulatory sequences while mSWI/SNF enzymes are required for the expression and binding of PAD enzymes. In vivo , the PADs contribute to mouse skeletal muscle regeneration after injury, with PAD4 specifically identified as a required regulator. This work identifies the PADs as critical cofactors in the initiation of skeletal muscle differentiation and reveals previously unappreciated connections between two major co-activator families during normal tissue development. Moreover, the results reveal important considerations for ongoing therapeutic approaches to myriad human diseases that utilize inhibitors of each enzyme family.

DOI: https://doi.org/10.64898/2026.01.20.700682
Intensive Care Med Exp. 2026 Feb 12. 14(1): 17

The impact of lipid-rich nutrition on ketogenesis and muscle weakness in sepsis.

Caroline Lauwers, Jan Gunst, Soraya El Dawy, Sarah Derde, Lies Pauwels, Inge Derese, Sarah Vander Perre, Greet Van den Berghe, Michael P Casaer, Lies Langouche.

   BACKGROUND: Administration of ketone bodies attenuated the severity of sepsis-induced muscle weakness in preclinical studies. Whether lipid-rich emulsions may likewise mitigate such muscle weakness by stimulating the endogenous ketogenic capacity remains uncertain, especially in relation to glucose, a critical suppressor of ketogenesis. This study investigated the ketogenic potential of parenteral nutrition rich in long- and/or medium-chain triglycerides with differing glucose content on sepsis-induced muscle weakness.
METHODS: We used a parenterally fed murine model of prolonged sepsis-induced muscle weakness to investigate specific lipid mixtures in two consecutive studies. Septic mice receiving standard total parenteral nutrition (TPN) and healthy control (HC) animals were included as references in both studies. In a first study, septic mice received pure long-chain triglycerides (LCT) or long-chain triglycerides supplemented with glucose (gLCT). The second study compared a gLCT mixture to a mixed medium- and long-chain triglyceride emulsion supplemented with glucose (gMCT). After 5 days of sepsis, markers of ketone body metabolism, muscle function, and muscle and liver metabolomics were measured.
RESULTS: In study one, ketosis was undetectable with TPN-treatment, but substantially increased with pure LCT (median 1.39 mmol/L, p < 0.001). Supplemental glucose suppressed ketosis sixfold (median 0.24 mmol/L, p < 0.001). The sepsis-induced muscle weakness was exacerbated in LCT mice, while muscle force was comparable between TPN-treated and gLCT mice (TPN 60.9%; gLCT 60.9%; LCT 33.1% of HC 128.7 mN/mm2, p < 0.001). The decrease in muscle glycolytic metabolites in LCT mice relative to TPN-treated mice was attenuated by supplemental glucose. In study 2, unexpectedly, ketosis was similarly low in gLCT and gMCT mice (p = 0.1), and muscle force was equally reduced in all septic groups (TPN 68.1%; gLCT 74.0%; gMCT 65.9% of HC 105.9 mN/mm2, p = 0.5) as compared to HC mice. Protein expression of the rate-limiting enzyme of ketogenesis, Hmgcs2, was suppressed in gMCT as compared to gLCT mice (p = 0.04).
CONCLUSIONS: Pure LCT infusion induced ketosis, but aggravated muscle weakness, which was attenuated by providing supplemental glucose. Combined with glucose, neither long-chain triglycerides nor mixed medium- and long-chain triglycerides were able to induce adequate ketosis or attenuate sepsis-induced muscle weakness.

Keywords:  Carnitine; Critical illness; Ketogenic diet; Ketones; Long-chain triglycerides; Medium-chain triglycerides; Muscle weakness; Sepsis

DOI:  https://doi.org/10.1186/s40635-026-00867-8
Autophagy. 2026 Feb 10. 1-2

Golgi fragmentation driven by the USP11-ITCH axis triggers autolysosomal failure in neurodegeneration.

Qiwang Xiang, Yang Liu, Jiou Wang.

  Golgi fragmentation is a prominent early hallmark of neurodegenerative diseases such as Alzheimer disease (AD) and amyotrophic lateral sclerosis (ALS), yet the shared molecular mechanisms underlying this phenomenon remain poorly understood. Here we identify the E3 ubiquitin ligase ITCH as a central regulator of Golgi integrity and proteostasis. Elevated ITCH disrupts both cis- and trans-Golgi networks, dislocates lysosomal hydrolase sorting factors, and impairs maturation of hydrolases. The ensuing lysosomal dysfunction leads to autophagosome accumulation and defective clearance of accumulated cytoplasmic toxic proteins like TARDBP/TDP-43. Genetic and pharmacological inhibition of ITCH restores autolysosomal degradation and protects neurons in both mammalian and Drosophila models. Aberrant buildup of the deubiquitinase USP11 drives ITCH accumulation, intensifying neuronal proteotoxic stress in individuals with AD and ALS. These findings reveal a mechanistic pathway connecting Golgi disorganization, autolysosomal impairment, and proteotoxic stress in neurodegeneration.

Keywords:  Autophagy; Golgi fragmentation; ITCH; USP11; lysosome; neurodegenerative diseases

DOI:  https://doi.org/10.1080/15548627.2026.2629295
bioRxiv. 2026 Jan 30. pii: 2026.01.29.702632. [Epub ahead of print]

Biological Mechanisms of Strength Preservation During Calorie Restriction-Induced Weight Loss Among Young- to Middle-Aged Adults without Obesity.

Nadia Moore, Akshay Bareja, Leanna M Ross, Katherine A Collins-Bennett, Susan B Racette, Leanne M Redman, Corby K Martin, Sai Krupa Das, William E Kraus, Kim M Huffman.

Purpose: Weight loss is often pursued to improve cardiometabolic health and quality of life. However, rapid weight loss can lead to reductions in lean soft tissue mass and strength to compromise body composition and functional ability. Thus, identifying molecular predictors of muscular strength preservation during weight loss is critical to mitigating these effects.
Methods: We conducted a secondary analysis of the CALERIE TM (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) trial, a two-year randomized controlled study of caloric restriction (CR) or ad-libitum intake in healthy adults without obesity. Among 198 participants, changes in whole-body mass and knee extensor strength were assessed over the first 12 months of the study which was primarily characterized by weight loss. Transcriptomic profiling was conducted in a subset of 42 participants who provided skeletal muscle samples. Linear regression was used to model the relationship between strength change and gene expression change, while controlling for changes in whole-body mass. Gene set enrichment analysis (GSEA) was performed using Hallmark pathways. Individual-level pathway analysis was performed via gene set variation analysis (GSVA).
Results: We identified 96 out of 198 individuals (48.5%) who maintained or improved strength relative to body mass during weight loss ( i.e. individuals with residuals > 0). Transcriptomics analysis on a subset of 42 individuals revealed 151 genes significantly associated with change in strength after accounting for change in whole-body mass ( p < 0.01). Hub genes were identified as HSP90AA1 (β = 34.45, SE = 7.32, p <0.001), EIF3A (β = 36.14, SE = 10.27, p < 0.001), EIF5B (β = 49.94, SE = 11.28, p < 0.001), and H3C1 (β = -15.87, SE = 4.85, p < 0.001). GSEA revealed significant involvement of pathways related to cellular proliferation, immune regulation, protein secretion, and checkpoint control processes. GSVA identified a similar set of pathways.
Conclusions: These findings highlight molecular pathways supporting strength retention during CR-induced weight loss. Heat-shock protein, HSP90AA1 , warrants further investigation as a candidate target for preserving muscle strength during interventions aimed at weight reduction.

DOI: https://doi.org/10.64898/2026.01.29.702632
bioRxiv. 2026 Jan 31. pii: 2026.01.28.701883. [Epub ahead of print]

A dose-dependent switch in translation capacity controls the transcription factor response to H 2 O 2 stress.

Chance Parkinson, Woody March-Steinman, Elizabeth Jose, Lisa Shanks, Andrew L Paek.

Hydrogen Peroxide (H 2 O 2 ) stress activates transcription factors (TFs) in a dose-dependent manner, with distinct TFs activated in response to low versus high H 2 O 2 . Here, we show that high H₂O₂ imposes a translational constraint that prevents accumulation of TFs requiring de novo protein synthesis. Under low H 2 O 2 conditions, TFs including p53, NRF2, and ATF4, accumulate and drive stress-responsive gene expression. In contrast, high H 2 O 2 induces coordinated inhibition of translation initiation and elongation through activation of the integrated stress response (ISR), suppression of mTORC1 signaling, and activation of eEF2K, thereby blocking accumulation of these TFs. Inhibition of translation and repression of p53, NRF2, and ATF4 coincides with nuclear shuttling of pre-existing TFs, including FOXO1, NFAT1, and NF-κB. We propose that shuttling TFs provide a backup mechanism to respond to severe oxidative stress while translation is inhibited. Together, these findings identify translational control as a central switch governing transcription factor response to H 2 O 2 stress.

DOI: https://doi.org/10.64898/2026.01.28.701883
Cell Death Dis. 2026 Feb 10.

Mitochondrial DNA drives NLRP3-IL-1β axis activation in microglia by binding to NLRP3, leading to neurodegeneration in Parkinson's disease models.

Qinglin Gan, Xiaolong Fu, Ting Zhou, Naiyu Fan, Nan Nan, Yi Wang, Yonggang Yang, Shiyi Gou, Lizhen Hu, Shaoyu Zhou.

Dysregulated mitochondrial DNA (mtDNA) promotes inflammatory response and disease progression. However, the mechanism and role of mtDNA-mediated inflammatory activation in the pathogenesis of Parkinson's disease (PD) are not yet clear. This study demonstrates that the injection of mtDNA into the substantia nigra pars compacta induces PD pathology in mice, characterized by the loss of dopaminergic (DA) neurons and the activation of microglia. Transcriptomic profiling of magnetic-activated cell sorting (MACS)-sorted cells reveals a pronounced upregulation of genes associated with the NLRP3 inflammasome pathway in microglia following the mtDNA administration. Critically, lipopolysaccharide (LPS) and rotenone induced in vivo and in vitro PD models show oxidized mtDNA (ox-mtDNA) release and microglial NLRP3-IL-1β axis activation as evidenced by upregulation of NLRP3 and IL-1β, caspase-1 cleavage, and IL-1β release. The role of mtDNA in activating the NLRP3-IL-1β axis is further validated in BV2 cells through exogeneous mtDNA transfection, while the NLRP3-IL-1β activation is negated in the LPS and rotenone induced model when mtDNA release is inhibited. Especially, oxidized mtDNA is superior to nonoxidized mtDNA in activating the NLRP3-IL-1β axis. NLRP3 knockdown in BV2 cells abolishes the activation of NLRP3-IL-1β axis induced by mtDNA or exposure of LPS and rotenone and mitigates the damage to SH-SY5Y cells in co-culture systems. Ox-mtDNA-mediated neuronal cell damage is initiated through binding to NLRP3, as demonstrated by co-immunoprecipitation and co-localization in BV2 cells. Molecular docking prediction and analysis of intrinsically disordered region (IDR) of NLRP3 indicate that ox-mtDNA interacts with the positively charged IDR of NLRP3. This interaction is validated by electrophoretic mobility shift and in vitro PYD-caspase-1 cleavage assays, demonstrating the formation of the ox-mtDNA-NLRP3 complex and subsequent activation of NLRP3. This study describes a critical role of mtDNA in activating microglial NLRP3-IL-1β axis, leading to neurodegeneration in PD pathology, which provides clear clues for developing anti-PD drugs targeting NLRP3.

DOI: https://doi.org/10.1038/s41419-026-08424-7
Adv Sci (Weinh). 2026 Feb 12. e23462

Illuminating Mitochondrial RNA G-Quadruplexes as Structural Brakes on RNA Granule Assembly and OXPHOS.

Gui-Xue Tang, Jia-Tong Yan, Mao-Lin Li, Cui Zhou, Jian Wang, Shuo-Bin Chen, Zhi-Shu Huang, Jia-Heng Tan.

  G-quadruplexes (G4s) have been extensively investigated in cells, with established methods available for studying nuclear DNA G4s, cytoplasmic RNA G4s, and even mitochondrial DNA G4s. However, mitochondrial RNA (mtRNA) G4s have remained largely unexplored in cells due to the lack of suitable tools, leaving their biological functions poorly understood. Here, through rational molecular design, we developed MitoQUMA, a fluorescent probe that allows the visualization of mtRNA G4 dynamics in live cells. Using this probe, we observed that, unlike cytoplasmic RNA G4s, which generally promote phase separation to form RNA granules, excessive formation of mtRNA G4s correlates with reduced assembly of mitochondrial RNA granules (MRGs). A MitoQUMA-based chemical genetic screen revealed that the Wnt/β-catenin pathway regulates this mitochondrial event by modulating GRSF1 expression, thereby affecting mtRNA G4 abundance and processing. When RNA processing is compromised, mtRNA maturation is impaired, and MRG becomes unstable and undergoes disassembly, ultimately disrupting mitochondrial gene expression and energy metabolism. Collectively, our study introduces a tool for real-time monitoring of mtRNA G4s in cells and identifies the Wnt/β-catenin-GRSF1-mtRNA G4 axis as a previously unrecognized pathway coordinating MRG assembly and energy metabolism, providing new insights into phase separation within mitochondria.

Keywords:  GRSF1; Wnt/β‐catenin pathway; mitochondrial RNA G‐quadruplex; mitochondrial RNA granule; molecular probe

DOI:  https://doi.org/10.1002/advs.202523462
Sci Adv. 2026 Feb 13. 12(7): eaec5134

Mechanical loading induces the longitudinal growth of muscle fibers via a rapamycin-insensitive mechanism.

Jamie E Hibbert, Kent W Jorgenson, Ramy K A Sayed, Hector G Paez, Marius Meinhold, Corey G K Flynn, Anthony N Lange, Garrison T Lindley, Philip M Flejsierowicz, Troy A Hornberger.

Mechanical loading drives skeletal muscle growth, yet the mechanisms that regulate this process remain undefined. Here, we show that an increase in mechanical loading induces muscle fiber growth through two distinct mechanisms. Radial growth, reflected by an increase in fiber cross-sectional area, is mediated through a rapamycin-sensitive signaling pathway, whereas longitudinal growth, marked by the in-series addition of sarcomeres, is mediated through a rapamycin-insensitive signaling pathway. To gain further insight into the events that drive longitudinal growth, we combined BONCAT-based labeling of synthesized proteins with high-resolution imaging and determined that the in-series addition of sarcomeres is mediated by a process that involves transverse splitting at the Z-lines of preexisting sarcomeres. Collectively, our findings not only challenge the long-standing view that mechanically induced growth is uniformly governed by mTORC1 but also lay the framework for a revised understanding of the molecular and structural events that drive this process.

DOI: https://doi.org/10.1126/sciadv.aec5134