bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–11–30
39 papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. Comprehensive transcriptomic analysis identifies Lrg1 as a potential therapeutic target for preventing muscle atrophy in cancer cachexia.
  2. C9ORF72 Is Pivotal to Maintain a Proper Protein Homeostasis in Mouse Skeletal Muscle.
  3. Oxytocin treatment reduces cancer cachexia in a pre-clinical model.
  4. Role of Cytokines and Inflammation in the Development of Cachexia in Cancer Patients.
  5. MitoQ supplementation does not impact redox responses to acute exercise in skeletal muscle of older individuals.
  6. Serum miRNA Signatures in Cancer Cachexia Depend on Systemic Inflammation.
  7. Restoring Muribaculum intestinale-Derived Butyrate Mitigates Skeletal Muscle Loss in Cancer Cachexia.
  8. The Age-Dependent Resident Myonuclear Multi-Omic Response to a Skeletal Muscle Hypertrophic Stimulus.
  9. Discovery of a Selective Inhibitor of ZIP14 with Therapeutic Potential for Cancer-associated Cachexia.
  10. Deficient Cardiolipin Remodeling Alters Muscle Fiber Composition and Neuromuscular Connectivity in Barth Syndrome.
  11. Mitochondrial capacities and quality control following short- and long-term weight restoration after simulated anorexia nervosa.
  12. Loss of cell-autonomously secreted laminin-α2 drives muscle stem cell dysfunction in LAMA2-related muscular dystrophy.
  13. Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging.
  14. Displaced myonuclei are attributable to both resident myonuclear migration and stem cell fusion during mechanical loading in adult skeletal muscle.
  15. MtDNA-depleted neuronal cell transcriptomes reveal Alzheimer's disease-related changes.
  16. Both skeletal muscle index and muscle attenuation are associated with frailty in preoperative older patients with pancreatic cancer.
  17. The Metabolome Atlas of 22 Tissues in Aging Mice Reveals a Switch in Thermogenesis from Brown Fat to Skeletal Muscle.
  18. Disruption of Rab9-dependent mitophagy contributes to menopause-induced sarcopenia.
  19. MicroCT enables simultaneous longitudinal tracking of murine pancreatic cancer progression and cachexia.
  20. Neuronal compartmentalization results in "impoverished" axonal mitochondria.
  21. A 16-amino acid peptide delays the progression of motor neuron degeneration and pathogenic symptoms in ALS models.
  22. Disulfiram inhibits Gasdermin D pores formation and improves insulin-dependent glucose uptake and glucose homeostasis in skeletal muscle of obesity-induced insulin-resistant mice.
  23. Targeting TOMM40 and TOMM22 to Rescue Statin-Impaired Mitochondrial Function, Dynamics, and Mitophagy in Skeletal Myotubes.
  24. Association of YY1 with STING activation and the inflammatory response during early muscle injury repair.
  25. Fiber Type and Stimulus Determine Progression of Skeletal Muscle Atrophy.
  26. Hypoxia-induced mitoROS triggers M1 linear ubiquitin chains and activates NF-κB signaling.
  27. The lysosomal carrier SLC29A3 supports antibacterial signaling, and promotes autophagy by activating TRPML1 in murine dendritic cells.
  28. Multiple Defects in Muscle Regeneration in the HSALR Mouse Model of RNA Toxicity.
  29. RAGE contributes to persistent sepsis-induced muscle and mitochondrial alterations.
  30. Single-nucleus and spatial transcriptomic profiling of human temporal cortex and white matter reveals key associations with AD pathology.
  31. IsomiR utility in amyotrophic lateral sclerosis prognostication.
  32. cGAS-STING-NF-κB Axis Mediates Rotenone-Induced NLRP3 Inflammasome Activation Through Mitochondrial DNA Release.
  33. Nicotinamide riboside supplementation restores microglial health and improves cognition in aged male mice.
  34. Inhibition of Mitochondrial Complex III Causes Dopaminergic Neurodegeneration by Redox Stress in Caenorhabditis elegans.
  35. Age- and Sex- Driven Transcriptional and Metabolic Diversity in Myeloid-Derived Suppressor Cells After Mouse Sepsis.
  36. Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
  37. ATP6V0D2 drives triple-negative breast cancer progression and inhibits cisplatin sensitivity by promoting PHLPP2 lysosomal degradation.
  38. KIF5A binds RNA to orchestrate synaptic mRNA localization and stress granules in ALS.
  39. Disruption of the insulin signaling pathway in C. elegans dramatically increases male longevity and enhances reproductive health late in life.
  1. Am J Physiol Cell Physiol. 2025 Nov 25.
    Comprehensive transcriptomic analysis identifies Lrg1 as a potential therapeutic target for preventing muscle atrophy in cancer cachexia.
    Hanbi Lee, Aeyung Kim, Kyuwon Son, Ahyoung Choi, Seongwon Cha, Hyunjin Shin, No Soo Kim, Haeseung Lee.
      Cancer cachexia is a debilitating syndrome characterized by progressive skeletal muscle wasting and systemic inflammation, primarily observed in patients with advanced-stage cancer. Cachexia severely impacts patients' quality of life and even increases mortality rates; however, effective therapeutic interventions remain elusive. To identify key mediators of muscle atrophy, we integrated more than one hundred bulk and single-cell transcriptomic datasets from diverse murine cachexia models, including colorectal, lung, and pancreatic cancer. This analysis identified leucine-rich alpha-2-glycoprotein 1 (Lrg1), as consistently upregulated in skeletal muscle endothelial cells across cachexia models and progressively increased during disease progression. Functional studies demonstrated that recombinant Lrg1 induced myotube atrophy in vitro, accompanied by reduced fusion index, shortened myotube length, and increased expression of the atrogenes MAFbx and MuRF1. Neutralization of Lrg1 or pharmacological inhibition of Stat3 prevented these effects. Our findings nominate Lrg1 as a candidate biomarker and potential therapeutic target for preventing skeletal muscle wasting in cancer cachexia.
    Keywords:  Lrg1; RNA sequencing; cancer cachexia; muscle atrophy; stat3
    DOI:  https://doi.org/10.1152/ajpcell.00319.2025
  2. Cells. 2025 Nov 11. pii: 1765. [Epub ahead of print]14(22):
    C9ORF72 Is Pivotal to Maintain a Proper Protein Homeostasis in Mouse Skeletal Muscle.
    Francesca Sironi, Paola Parlanti, Cassandra Margotta, Jessica Cassarà, Valentina Bonetto, Caterina Bendotti, Massimo Tortarolo, Valentina Cappello.
      The C9ORF72 gene mutation is a major cause of amyotrophic lateral sclerosis (ALS). Disease mechanisms involve both loss of C9ORF72 protein function and toxic effects from hexanucleotide repeat expansions. Although its role in neurons and the immune system is well studied, the impact of C9ORF72 deficiency on skeletal muscle is not yet well understood, despite muscle involvement being a key feature in ALS pathology linked to this mutation. This study examined skeletal muscle from C9ORF72 knockout mice and found a 19.5% reduction in large muscle fibers and altered fiber composition. Ultrastructural analysis revealed mitochondrial abnormalities, including smaller size, pale matrix, and disorganized cristae. Molecular assessments showed increased expression of Atrogin-1, indicating elevated proteasomal degradation, and markers of enhanced autophagy, such as elevated LC3BII/LC3BI ratio, Beclin-1, and reduced p62. Mitochondrial quality control was impaired, with a 3.6-fold increase in PINK1, upregulation of TOM20, reduced Parkin, and decreased PGC-1α, suggesting disrupted mitophagy and mitochondrial biogenesis. These changes led to the accumulation of damaged mitochondria. Overall, the study demonstrates that C9ORF72 is critical for maintaining muscle protein and mitochondrial homeostasis. While C9orf72-haploinsufficiency does not directly compromise muscle strength in mice, it may increase the vulnerability of skeletal muscle in C9ORF72-associated ALS.
    Keywords:  amyotrophic lateral sclerosis; atrogenes; autophagy; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.3390/cells14221765
  3. Biomed Pharmacother. 2025 Nov 25. pii: S0753-3322(25)01019-4. [Epub ahead of print]193 118825
    Oxytocin treatment reduces cancer cachexia in a pre-clinical model.
    Alexandra Sviercovich, Etsuko Watanabe, Estefania S Fernandez, Alessandra Renzini, Chao Liu, Grace Xie, Jasmine Cao, Zhenlin Li, Onnik Agbulut, Marilia Seelaender, Jose Pinhata Otoch, Daniele De Meo, Gianluca Cera, Viviana Moresi, Francesca Palermo, Sergio Adamo, Michael J Conboy, Irina M Conboy, Dario Coletti.
      Oxytocin (OT) is a neurohypophyseal peptide with decreased expression during aging, essential for skeletal muscle homeostasis, and counteracts sarcopenia in aged mice. Yet, its function in cancer cachexia remains unexplored. We investigated OT serum levels in cancer patients, comparing these with cachectic patients and non-cancer controls, as well as OT/OT-receptor (OTR) mRNA in sarcopenic muscle. Potential benefits of OT were assessed in vitro using L6C5 myoblasts and murine isolated myofibers exposed to C26-conditioned medium and in vivo using the C26/Balb/c cancer cachexia model. Finally, the molecular effects of OT on de novo protein synthesis via bio-orthogonal non-canonical amino acid tagging (BONCAT) were investigated using MetRSL274G C57BL/6 mice. Circulating OT was significantly lower in cancer patients than in non-cancer disease (-60 %, p < 0.01). Sarcopenic muscle showed over threefold downregulation of the OTR (p < 0.032). In vitro, OT reversed the myogenic inhibition induced by tumor cell-conditioned medium, boosting fusion index (>6-fold, p < 0.001), nuclei per myotube (>8-fold, p < 0.001), and myotube diameter (>6-fold, p < 0.001). In C26 tumor-bearing mice, OT restored skeletal muscle mass (>1.5-fold, p < 0.001), fiber cross-sectional area (>1.5-fold, p < 0.001), and overall body weight, while reducing the muscle degradation determinants: MuRF1 (>8-fold, p < 0.001) and Atrogin1 (>6-fold, p < 0.001). Metabolic proteomics showed that cancer perturbed and OT restored the synthesis of key proteins (+23 %, p < 0.05) that play essential roles in muscle regeneration and inter-organ communication. Given that OT is approved for clinical use, our findings suggest that it could quickly be translated into effective therapies for preventing or treating cachexia in cancer patients.
    Keywords:  BONCAT; Cancer cachexia; Oxytocin; Protein metabolism
    DOI:  https://doi.org/10.1016/j.biopha.2025.118825
  4. Indian J Surg Oncol. 2025 Oct;16(5): 970-977
    Role of Cytokines and Inflammation in the Development of Cachexia in Cancer Patients.
    Vanessa Fuchs-Tarlovsky, Fernand Vedrenne-Gutierrez.
      Cytokines are secreted in response to infection, trauma, or malignancy. Cancer results when cells can no longer regulate their proliferation and differentiation. Cell processes that are linked to cancer development involve bypassing apoptosis, growth suppressors, and immune system regulation, developing new vasculature (angiogenesis), and metabolic changes. Many of these processes involve cytokine signaling and crosstalk between cancer cells and immune cells. The effects of cytokines on cancer patients can be complex and depend on many factors, including the type and stage of cancer, the patient's immune status, and the specific cytokines involved. Understanding the role of cytokines in cancer is an active area of research, and new therapies targeting cytokines are being developed to improve cancer treatments. More than half of the patients with cancer develop cachexia. This condition is related to the role of cytokines and mediators in creating this specific environment. Cancer cachexia is a complex syndrome characterized by the loss of skeletal muscle mass with or without loss of fat mass which cannot be fully reversed using standard nutritional care and affects outcomes, response to cancer treatments, survival, and quality of life. Cytokines play a crucial role in the development of cancer cachexia, and targeting cytokine signaling pathways may be a promising approach for the prevention and treatment of this debilitating condition in cancer patients.
    Keywords:  Cancer; Cancer cachexia; Cytokines; Inflammation
    DOI:  https://doi.org/10.1007/s13193-025-02212-z
  5. Redox Biol. 2025 Nov 14. pii: S2213-2317(25)00440-9. [Epub ahead of print]88 103927
    MitoQ supplementation does not impact redox responses to acute exercise in skeletal muscle of older individuals.
    Sophie C Broome, Jamie Whitfield, Kristel Janssens, John A Hawley.
      Ageing is associated with attenuated exercise responses in skeletal muscle, which may be related to a failure of muscle redox signalling. The attenuation of redox responses to exercise in aged muscle has been linked to perturbations in redox homeostasis induced by age-related increases in mitochondrial oxidative stress. Accordingly, we investigated the effects of supplementation with the mitochondria-targeted antioxidant MitoQ on mitochondrial bioenergetics and H2O2 emission as well as acute exercise-induced redox responses in skeletal muscle of older individuals. In a randomised, double-blind, placebo-controlled, parallel design, 10 males and 12 females aged 65-80 years were randomised to receive either MitoQ (20 mg/day) or a placebo for 12 weeks before completing a single bout of exercise. Vastus lateralis muscle biopsies were collected before supplementation and before, immediately post- and 4 h post-exercise. MitoQ supplementation reduced mitochondrial H2O2 emission capacity in skeletal muscle but did not impact mitochondrial respiration, H2O2 emission in the presence of ADP, or the sensitivity for ADP to stimulate respiration (apparent Km) and attenuate H2O2 emission (apparent IC50). Acute exercise-induced peroxiredoxin oxidation in skeletal muscle was not altered by MitoQ supplementation. Similarly, MitoQ had no effect on the phosphorylation of several redox-sensitive protein kinases (AMPK, p38 MAPK, and ERK1/2) or the upregulation of mitochondrial and antioxidant genes following exercise. Collectively, these findings indicate that MitoQ supplementation did not influence the basal myocellular redox state or redox responses to exercise in skeletal muscle of older individuals.
    Keywords:  Ageing; Antioxidant; Mitochondria; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.redox.2025.103927
  6. Curr Oncol. 2025 Nov 06. pii: 620. [Epub ahead of print]32(11):
    Serum miRNA Signatures in Cancer Cachexia Depend on Systemic Inflammation.
    Terese Louise Schmidberger Karlsen, Robin Mjelle, Ola Magne Vagnildhaug, Trude Rakel Balstad, Are Korsnes Kristensen, Jens Erik Slagsvold, Ganna S Westwik, Hege Elvebakken, Eva Hofsli, Ingunn Hatlevoll, Tora Skeidsvoll Solheim.
      Cancer cachexia is a complex syndrome marked by involuntary weight and muscle loss, often driven by systemic inflammation. This multicenter, longitudinal observational study investigated circulating microRNA (miRNA) profiles in patients with unresectable locally advanced or metastatic colorectal cancer, comparing those with and without cachexia and inflammation. A total of 168 patients were categorized into four groups based on cachexia and C-reactive protein (CRP) levels. Cachexia was defined using the 2011 consensus criteria, incorporating weight loss, low BMI, and sarcopenia. Patients with both cachexia and systemic inflammation exhibited significantly distinct miRNA profiles as well as poorer overall survival (HR 2.10, p < 0.001) compared to patients with neither condition. No significant differences were observed in patients lacking either cachexia or inflammation or both. Inflammatory cachexia emerged as a biologically distinct entity, with 82 differentially expressed miRNAs. The miR-320-family, miR-6087, miR-4488, miR-29a-3p, miR-194-5p, and miR-10a-5p were most altered, several of which are linked to muscle mass, metabolism, lipid, and protein synthesis. These findings highlight the pivotal role of systemic inflammation in cancer cachexia and support its inclusion in diagnostic criteria. Moreover, circulating miRNAs may serve as promising biomarkers for identifying cachexia in cancer patients.
    Keywords:  MiRNA; biomarkers; cachexia; cancer; colorectal cancer; inflammation
    DOI:  https://doi.org/10.3390/curroncol32110620
  7. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70140
    Restoring Muribaculum intestinale-Derived Butyrate Mitigates Skeletal Muscle Loss in Cancer Cachexia.
    Li Li, Panpan Lian, Wei Dong, Shiyu Song, Junaid Wazir, Ranran Wang, Kai Lin, Wenyuan Pu, Renwei Lu, Zhenghong Yu, Chao Ding, Zhiqiang Huang, Yong Wang, Hongwei Wang.
       BACKGROUND: Muscle wasting in cancer cachexia patients is a major clinical challenge. Although reduced levels of short-chain fatty acids (SCFAs) in cachexia patients have been associated with muscle atrophy, their precise role remains unclear. Given that the gut microbiota is the primary source of SCFAs, modulating SCFA composition through probiotic supplementation has shown promise in preclinical studies of cancer cachexia. In this study, we aimed to elucidate the dysregulation of the gut microbiota in cachexia mice and investigate the potential protective effect of supplementation with the inulin diet, Muribaculum intestinale (MI) and sodium butyrate (NaB) against cachexia-induced muscle wasting.
    METHODS: We analysed the gut microbiota composition using 16S rRNA gene amplicon sequencing and measured SCFA levels to evaluate metabolic changes in faecal samples from cancer cachexia models. We identified the associations between the microbiota and metabolites and evaluated the impacts of MI (108 CFU per mouse), NaB (50 mg/kg) and inulin diet on cancer cachexia models. The mechanism of NaB was elucidated by muscle RNA-Seq and confirmed by Western blotting, qPCR, ATP assays and other experimental approaches, revealing the effects of altered gut microbiota composition and metabolite levels on muscle metabolism in cachectic mouse models.
    RESULTS: Faecal analysis in cachectic mice revealed a significant alteration in gut microbiota composition, particularly a reduction in Muribaculaceae (76.0%) and Muribaculum intestinale (82.0%). Direct supplementation with MI increased its abundance and butyrate level (p < 0.05), reducing muscle wasting in cachexia. Correlation analysis underscored a significant positive association between Muribaculaceae, Muribaculum intestinale and butyrate levels (p < 0.05). NaB also ameliorated muscle wasting, with RNA-Seq of muscle tissues showing a decrease in inflammatory factors and autophagy, downregulation of pyruvate dehydrogenase kinase 4 (Pdk4) expression (61.6%) and increased ATP content (25.5%), thereby playing a pivotal role in attenuating muscle degradation in cancer cachexia. Supplementation with inulin diet increased the levels of Muribaculaceae and Muribaculum intestinale (p < 0.05), also alleviating cachexia symptoms in mice.
    CONCLUSIONS: In cachectic mouse models, Muribaculaceae and Muribaculum intestinale are reduced and exhibit a significant positive correlation with SCFA butyrate. Inulin or MI supplementation increased these bacteria, ameliorating cachexia. NaB attenuates muscle wasting through coordinated modulation of autophagy suppression, anti-inflammatory effects and metabolic reprogramming (including PDK4 downregulation and ATP elevation), collectively indicating the existence of a gut-muscle axis in cachexia progression. These findings underscore the potential of microbiota-targeted interventions in managing cancer cachexia and highlight the intricate interplay between gut microbiota and skeletal muscle health.
    Keywords:   Muribaculaceae ; Muribaculum intestinale ; cancer cachexia; gut microbiota; muscle atrophy; short‐chain fatty acid
    DOI:  https://doi.org/10.1002/jcsm.70140
  8. bioRxiv. 2025 Oct 30. pii: 2025.10.29.685384. [Epub ahead of print]
    The Age-Dependent Resident Myonuclear Multi-Omic Response to a Skeletal Muscle Hypertrophic Stimulus.
    Pieter J Koopmans, Ronald G Jones, Ana Regina Cabrera, Francielly Morena, Nicholas P Greene, John J McCarthy, Ahmed Ismaeel, Yuan Wen, Kevin A Murach.
      A detailed analysis of how muscle fiber nuclei (myonuclei) respond to a hypertrophic stimulus would provide a critical step toward understanding compromised skeletal muscle plasticity with age. We used recombination-independent doxycycline-inducible myonucleus-specific fluorescent labelling, tissue RNA-sequencing, myonuclear DNA methylation analysis, multi-omic integration, and single myonucleus RNA-sequencing to define the molecular characteristics of adult (6-8 month) and aged (24 month) murine skeletal muscle after acute mechanical overload (MOV). In adult and aged MOV muscles, we found that: 1) similarities in the transcriptional response to loading - specifically in metabolism genes - were partly explained by a post-transcriptional microRNA-mediated mechanism, which we corroborated using an inducible muscle fiber-specific miR-1 knockout model, 2) differences in age-dependent transcriptional responses were linked to the magnitude and location of differential DNA methylation in resident myonuclei, specifically around hypertrophy-associated genes such as Myc , Runx1 , Mybph , Ankrd1, collagen genes, and minichromosome maintenance genes, 3) adult and aged resident myonuclear transcriptomes had differing enrichment for innervation-related transcripts as well as unique transcriptional profiles in an Atf3+ "sarcomere assembly" population after MOV, and 4) cellular deconvolution analysis supports a role for neuromuscular junction regulation in age-specific hypertrophic adaptation. These data are a roadmap for uncovering molecular targets to enhance aged muscle adaptability.
    DOI:  https://doi.org/10.1101/2025.10.29.685384
  9. bioRxiv. 2025 Oct 23. pii: 2025.10.23.682519. [Epub ahead of print]
    Discovery of a Selective Inhibitor of ZIP14 with Therapeutic Potential for Cancer-associated Cachexia.
    Takafumi Hara, Gen Tanaka, Tomonori Tamura, Masaomi Terajima, Kengo Hamamura, Yuya Yoshida, Toru Kimura, Yusuke Kasai, Yuta Nakayama, Takumi Umeyama, Kohei Hosoi, Ayaka Noguchi, Yasuno Nakai, Atsushi Hijikata, Koji Matsukawa, Satoru Ujihara, Tetsuhiro Kawabe, Hiroki Taguchi, Hitomi Fujishiro, Supak Jenkitkasemwong, Kazuto Nunomura, Bangzhong Lin, Ayako Fukunaka, Emi Yoshigai, Kenji Mishima, Shinsaku Nakagawa, Michell D Knutson, Hiroshi Imagawa, Naoya Matsunaga, Shigehiro Ohdo, Itaru Hamachi, Hiroyuki Sakurai, Toshiyuki Fukada.
      ZIP14/SLC39A14, a membrane-bound metal transporter, is essential for systemic metal homeostasis and has been implicated in inflammatory and metabolic disorders, including cancer-associated cachexia. Despite its biological and therapeutic significance, no selective inhibitors have been identified. Here, we identify 1-phenyl-8-(2-phenylethyl)-1,3,8-triazaspiro[4.5]decan-4-one (PPTD) as the first selective small-molecule inhibitor of ZIP14. PPTD efficiently blocks ZIP14-mediated uptake of zinc, iron, manganese, and cadmium, while sparing the closely related transporter ZIP8/SLC39A8. Mechanistically, PPTD binds specifically to a pocket formed at the dimer interface of ZIP14, as revealed by AlphaFold3 structural prediction, ligand-interaction profiling, structure-activity analyses, and site-directed mutagenesis, providing direct evidence for a targeted inhibition mechanism. ZIP14-driven metal influx promotes reactive oxygen species and lipid peroxidation, leading to cytotoxicity, which PPTD effectively reverses. In vivo , PPTD ameliorates major features of cancer cachexia in mice, including weight loss, reduced survival, muscle wasting, impaired locomotor activity, and disease progression. PPTD thus provides both a chemical probe to dissect ZIP14 function and a potential therapeutic candidate for cancer cachexia, establishing a foundation for the development of therapies targeting ZIP14-mediated metal dysregulation.
    DOI:  https://doi.org/10.1101/2025.10.23.682519
  10. bioRxiv. 2025 Nov 03. pii: 2025.10.31.685856. [Epub ahead of print]
    Deficient Cardiolipin Remodeling Alters Muscle Fiber Composition and Neuromuscular Connectivity in Barth Syndrome.
    Catalina Matias, Paige L Snider, Elizabeth A Sierra Potchanant, Joshua R Huot, Rahul Raghav, Michael T Chin, Simon J Conway, Jeffrey J Brault.
       Background: Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by mutations in the TAFAZZIN gene, which disrupts cardiolipin (CL) remodeling and mitochondrial function. While cardiac manifestations of BTHS are well characterized, the mechanisms underlying skeletal muscle weakness and fatigability are poorly understood.
    Methods: We investigated neuromuscular and mitochondrial alterations in a novel murine model (Taz PM ) carrying a patient-derived D75H point mutation in Tafazzin . This mutation preserves protein abundance but abolishes enzymatic activity. Skeletal muscle function was assessed via weightlifting and hanging tests. Muscle fiber composition and neuromuscular junction (NMJ) integrity were evaluated using immunofluorescence, western blotting, and in vivo electrophysiology. Mitochondrial morphology was examined by transmission electron microscopy, and bioenergetics were quantified using ultra-performance liquid chromatography. Stress signaling was assessed by western blotting.
    Results: Male Taz PM mice exhibited elevated monolysocardiolipin and reduced mature CL levels, confirming deficient transacylase activity. These mice exhibited lower muscle strength and endurance, smaller muscle fibers of all types, and a shift toward fast-twitch type 2B fibers, which are more susceptible to fatigue. Electrophysiological analysis revealed a 60% reduction in motor unit number and an increase in average single motor unit potential, indicating motor neuron remodeling. NMJ protein analysis showed decreased MUSK and DOK7 and increased CHRNA1, suggesting impaired NMJ integrity. Despite mitochondrial structural abnormalities and reduced expression of key mitochondrial proteins (NDUFB8, MCU, TMEM65), resting ATP, phosphocreatine, and adenine nucleotide ratios were unchanged in both glycolytic and oxidative muscles. However, stress signaling pathways were markedly activated, including phosphorylation of eIF2α, increased CHOP, DELE1, p53 expression, and altered Wnt/β-catenin signaling components.
    Conclusions: Deficiency of Tafazzin enzymatic activity in skeletal muscle is sufficient to result in widespread neuromuscular remodeling, including fiber size/type shifts, motor unit loss, NMJ dysregulation, and stress pathway activation, without overt energetic failure at rest. These findings suggest that myopathy in BTHS arises not solely from mitochondrial ATP insufficiency but rather from cumulative structural and signaling disruptions.
    DOI:  https://doi.org/10.1101/2025.10.31.685856
  11. Exp Physiol. 2025 Nov 29.
    Mitochondrial capacities and quality control following short- and long-term weight restoration after simulated anorexia nervosa.
    Megan E Rosa-Caldwell, Toby L Chambers, Lauren Breithaupt, Ruqaiza Muhyudin, Patience Salvalina Okoto, Sadie R Thompson, Emily E Rothacker, Claire Greenhill, Katie A Wood, Kevin A Murach, Sarah H White-Springer, Ursula B Kaiser, Seward B Rutkove.
      Anorexia nervosa (AN) is a psychiatric disorder characterized by prolonged caloric restriction and skeletal muscle atrophy. Mitochondrial health is a key mediator of muscle function, yet the role of mitochondria during AN and following weight regain has not been investigated. The objective of this study was to evaluate mitochondrial capacities and quality control mechanisms in a rodent model of AN, spanning the acute underweight phase and multiple recovery periods. Through a series of experiments, 8-week-old female Sprague-Dawley rats underwent a 30-day simulated AN protocol, followed by different durations of weight recovery via ad libitum feeding. Following designated interventions, muscle performance on a submaximal fatiguing protocol and components of mitochondrial function were evaluated. AN resulted in 23%-25% lower muscle performance compared to healthy controls, and these alterations remained even after short-term weight gain. AN rats had 23% lower contribution of complex I to maximal mitochondrial electron transfer as well as alterations to genes important for mitochondrial translation and dynamics, many of which were not resolved with short-term recovery. With long-term recovery, muscle performance and mRNA content of genes related to mitochondrial translation were similar to healthy controls. However, genes related to mitochondrial fission were greater than healthy controls. AN results in reduced muscle performance during a fatiguing protocol, reliance on mitochondrial complex I and genes related to mitochondrial quality control. Many alterations persist with short-term weight recovery; however, given sufficient time, many facets of mitochondrial health appear to normalize following AN, though there still may be long-term consequences to mitochondrial dynamics.
    Keywords:  mitochondrial biogenesis; mitochondrial dynamics; mitochondrial translation; mitophagy; muscle fatigability; starvation
    DOI:  https://doi.org/10.1113/EP093325
  12. Nat Commun. 2025 Nov 27. 16(1): 10674
    Loss of cell-autonomously secreted laminin-α2 drives muscle stem cell dysfunction in LAMA2-related muscular dystrophy.
    Timothy J McGowan, Judith R Reinhard, Nicolas Lewerenz, Marta Białobrzeska, Shuo Lin, Jacek Stępniewski, Krzysztof Szade, Józef Dulak, Markus A Rüegg.
      The extracellular matrix protein laminin-α2 is essential for preserving the integrity of skeletal muscle fibers during contraction. Its importance is reflected by the severe, congenital LAMA2-related muscular dystrophy (LAMA2 MD) caused by loss-of-function mutations in the LAMA2 gene. While laminin-α2 has an established role in structurally supporting muscle fibers, it remains unclear whether it exerts additional functions that contribute to the maintenance of skeletal muscle integrity. Here, we report that in healthy muscle, activated muscle stem cells (MuSCs) express Lama2 and remodel their microenvironment with laminin-α2. By characterizing LAMA2 MD-afflicted MuSCs and generating MuSC-specific Lama2 knockouts, we show that MuSC-derived laminin-α2 is essential for rapid MuSC expansion and regeneration. In humans, we identify LAMA2 expression in MuSCs and demonstrate that loss-of-function mutations impair cell-cycle progression of myogenic precursors. In summary, we show that self-secreted laminin-α2 supports MuSC proliferation post-injury, thus implicating MuSC dysfunction in LAMA2 MD pathology.
    DOI:  https://doi.org/10.1038/s41467-025-65703-1
  13. Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2508893122
    Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging.
    Sze Mun Choy, Kah Yong Goh, Wen Xing Lee, Weiyi Jiang, Qian Gou, Priya D Gopal Krishnan, Shi Chee Ong, Kenon Chua, Nathan Harmston, Hong-Wen Tang.
      Skeletal muscle is essential for movement, respiration, and metabolism, with mTORC1 acting as a key regulator of protein synthesis and degradation. In aging muscle, mTORC1 becomes overactivated, contributing to sarcopenia, though the mechanisms remain unclear. Here, we identify DEAF1, a FOXO-regulated transcription factor, as a key upstream driver of mTORC1 in aged muscle. Elevated Deaf1 expression increases mTOR transcription, leading to heightened mTORC1 activity, impaired proteostasis, and muscle senescence. Remarkably, exercise suppresses Deaf1 expression via FOXO activation, restoring mTORC1 balance and alleviating muscle aging. Conversely, FOXO inhibition or Deaf1 overexpression blocks exercise benefits on muscle health. These findings highlight DEAF1 as a critical link between FOXO and mTORC1 and suggest that targeting the FOXO-DEAF1-mTORC1 axis may offer therapeutic potential to preserve muscle function during aging.
    Keywords:  autophagy; mTORC1; muscle; proteostasis; sarcopenia
    DOI:  https://doi.org/10.1073/pnas.2508893122
  14. bioRxiv. 2025 Oct 11. pii: 2025.10.10.681647. [Epub ahead of print]
    Displaced myonuclei are attributable to both resident myonuclear migration and stem cell fusion during mechanical loading in adult skeletal muscle.
    Nathan Serrano, Pieter Jan Koopmans, Kevin A Murach.
      Non-peripheral myonuclei are characteristic of skeletal muscle pathology and severe injury but also appear after exercise and with aging. Displaced myonuclei are typically attributed to the activity of muscle stem cells, or satellite cells. We sought to address whether displaced myonuclei in adult skeletal muscle are exclusively from an exogenous source such as satellite cells or can result from resident myonuclear migration. To address this question, we used a murine recombination-independent muscle fibre-specific doxycycline-inducible fluorescent myonuclear labelling approach, EdU stem cell fate tracking, two durations of muscle mechanical overload (MOV, 3 days and 7 days), and fluorescent histology. Our findings show that: 1) displaced myonuclei emerge early during MOV, 2) resident myonuclear movement occurs rapidly during MOV, and 3) the contribution of resident versus exogenous displaced myonuclei depends on MOV duration, fibre type, and fibre size. These observations provide fundamental insights on myonuclear motility in response to stress in vivo and reframe our understanding of how a recognized feature of mammalian skeletal muscle can emerge in response to mechanical loading.
    Summary: Recombination-independent muscle fibre-specific doxycycline-inducible fluorescent myonuclear labelling in adult mice unambiguously reveals how resident myonuclei relocate rapidly during stress and contribute to the appearance of displaced myonuclei.
    DOI:  https://doi.org/10.1101/2025.10.10.681647
  15. Alzheimers Dement. 2025 Nov;21(11): e70929
    MtDNA-depleted neuronal cell transcriptomes reveal Alzheimer's disease-related changes.
    Blaise W Menta, Emily Schueddig, Amol Ranjan, Yanming Li, Shea J Andrews, Heather M Wilkins, Dong Pei, Russell H Swerdlow.
       INTRODUCTION: We determined whether mitochondrial DNA (mtDNA) depletion induced Alzheimer's disease (AD)-relevant transcription changes.
    METHODS: Following RNA sequencing (RNA-seq), we identified differentially expressed genes (DEGs) between SH-SY5Y or NT2 mtDNA-depleted (ρ0) and intact (ρ+) cell lines and quantified concordant DEG changes. Gene set enrichment analysis and over-representation analysis were used to determine the impact on the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD and other neurodegenerative disease pathways, ascertain pathway and term enrichment in the Reactome and Gene Ontology databases, and generate Ingenuity Pathway Analysis z-scores.
    RESULTS: Relative to their ρ+ comparators, ρ0 lines differentially expressed >75% of their genes. The KEGG AD pathway was significantly enriched, and equivalently altered genes ranked the AD, Parkinson's disease, ALS, and Huntington's disease KEGG pathways among the most enriched gene sets. AD-related enriched pathways and terms reflected lipid, insulin signaling, synapse, inflammation/immune response, endosome/endocytosis, RNA, and proteostasis biology.
    CONCLUSION: MtDNA depletion alters gene expression in ways that recapitulate or predictably promote AD molecular phenomena.
    HIGHLIGHTS: MtDNA-depleted neuronal cell lines reshuffle nuclear gene expression. The KEGG AD pathway is enriched with DEGs. Transcription-defined pathways and terms relating to AD biology broadly change.
    Keywords:  Alzheimer's disease; RNA sequencing; mitochondria; mitochondrial DNA; transcriptome
    DOI:  https://doi.org/10.1002/alz.70929
  16. Clin Nutr. 2025 Nov 21. pii: S0261-5614(25)00298-5. [Epub ahead of print]55 242-248
    Both skeletal muscle index and muscle attenuation are associated with frailty in preoperative older patients with pancreatic cancer.
    Claudia J Lucassen, Yaren Zügül, Anneke Droop, Bert A Bonsing, Alexander L Vahrmeijer, Nynke Michiels, Shirin Shahbazi Feshtali, E T Daniël Souwer, Johanneke E A Portielje, J Sven D Mieog, Frederiek van den Bos.
       BACKGROUND AND AIMS: Frailty and sarcopenia are associated with morbidity and mortality in older patients with cancer. The aim of this study was to examine the association of frailty with skeletal muscle index (SMI) and muscle attenuation (MA) on preoperative CT-scans in older patients with pancreatic cancer.
    METHODS: A single-center retrospective study was performed in patients aged ≥70 years with pancreatic cancer. Frailty was assessed by an abbreviated GA screening. Preoperative SMI and MA were determined by computed tomography (CT) scan analysis. The association of frailty and individual frailty domains with SMI and MA was assessed using linear regression analyses.
    RESULTS: 101 patients were included of which 15 (14.9 %) were frail. Frailty was associated with lower SMI (adjusted β: -5.07 cm2/m2; 95 % CI: -8.77-1.36) and MA (adjusted β: -5.70 HU; 95 % CI: -9.63-1.77). Both impaired functionality and risk of delirium were associated with lower SMI (adjusted β: -7.01 cm2/m2; 95 % CI: -11.69-2.33 and adjusted β: -4.58 cm2/m2; 95 % CI: -8.22-0.95, respectively). Impaired functionality was also associated with lower MA (adjusted β: -6.88 HU; 95 % CI: -11.89-1.87).
    CONCLUSION: Frailty and impaired functionality were associated with lower SMI and MA. Risk of delirium was independently associated with lower SMI in preoperative older patients with pancreatic cancer. These results suggests that SMI and MA should be included in standard GA screening to better identify high-risk patients and enable more targeted treatment selection.
    Keywords:  Computed tomography; Frailty; Older patients; Pancreatic cancer; Sarcopenia
    DOI:  https://doi.org/10.1016/j.clnu.2025.11.004
  17. Res Sq. 2025 Oct 29. pii: rs.3.rs-7811947. [Epub ahead of print]
    The Metabolome Atlas of 22 Tissues in Aging Mice Reveals a Switch in Thermogenesis from Brown Fat to Skeletal Muscle.
    Oliver Fiehn, Min Liu, Jian Ji, Anthony David, Huaxu Yu, Tong Shen, Yuanyue Li, Lydia Yang.
      Aging impairs thermoregulatory capacity, yet the metabolic mechanisms remain unclear. We report an organ-resolved metabolome atlas of 2,875 structurally annotated metabolites of old (90-96 weeks) versus young mice (16 weeks) across 22 tissues and four biological matrices. For thermoregulation, aging induces widespread remodeling of mitochondrial cardiolipins, with severe depletion of nascent species in brown adipose tissue (BAT) and a compensatory shift in thermogenic workload from BAT to muscle, evidenced by higher levels of long-chain fatty acids, acylcarnitines, and ω-oxidation markers in quadriceps. BAT showed reduced lipolysis and lower levels of the thermogenic lipokine 12,13-DiHOME, whereas muscle exhibited increased 12,13-DiHOME, lipid uptake, β-oxidation, and stress-associated metabolites including oxidized/reduced glutathione ratio. Hence, thermogenic adaptation comes at a cost: aged muscles exhibited signs of proteostatic stress, energetic strain, and oxidative damage, suggesting compensation contributes to sarcopenia. The atlas is publicly available at GitHub https://github.com/minliuUCDavis/AgingMiceAtlas and serves as a cornerstone resource for aging biology.
    DOI:  https://doi.org/10.21203/rs.3.rs-7811947/v1
  18. Exp Gerontol. 2025 Nov 20. pii: S0531-5565(25)00299-2. [Epub ahead of print] 112970
    Disruption of Rab9-dependent mitophagy contributes to menopause-induced sarcopenia.
    Shota Uebo, Yoshiyuki Ikeda, Yoshihiro Uchikado, Yuichi Sasaki, Yuichi Akasaki, Takuro Kubozono, Mitsuru Ohishi.
      Aim Sarcopenia, a major cause of frailty in postmenopausal women, is linked to mitochondrial dysfunction, but the underlying mechanisms remain unclear. This study aimed to clarify whether mitophagy, a mitochondrial quality control mechanism, contributes to postmenopausal sarcopenia, to elucidate its underlying mechanism, and to assess whether it can be rescued.
    METHODS: C57BL/6 mice (12-week-old females) underwent ovariectomy to establish a menopause mouse model, or sham surgery, and the therapeutic effects of nicotinamide mononucleotide (NMN) were assessed. Human skeletal muscle myoblasts (HSMMs) differentiated under postmenopausal conditions with or without 17β-estradiol (E2), and Rab9 expression was modulated using CRISPR activation.
    RESULTS: Ovariectomized mice exhibited decreased muscle mass and strength. E2 deficiency in HSMMs inhibited skeletal muscle cell differentiation, promoted senescence, impaired mitochondrial function, and reduced mitophagy. However, E2 deficiency did not modulate light chain 3 and autophagy-related 7 but reduced Rab9 expression and the colocalization of Rab9 with lysosomal-associated membrane protein 2, suggesting that E2 mediates mitophagy through Rab9-dependent alternative autophagy. Furthermore, overexpression of Rab9 in E2-deficient HSMMs enhanced mitophagy, improved mitochondrial function, suppressed cellular senescence, and promoted skeletal muscle cell differentiation. The administration of NMN to ovariectomized mice increased Rab9 expression and improved sarcopenia through increased mitophagy.
    CONCLUSION: This study demonstrates that estrogen deficiency impairs mitophagy originated from Rab9-dependent alternative autophagy, leading to mitochondrial dysfunction and sarcopenia, while enhancement of Rab9 restores mitochondrial quality control and muscle function. These results identify Rab9-dependent mitophagy as a potential therapeutic target for postmenopausal sarcopenia.
    Keywords:  Alternative autophagy; Estrogen; Menopause-induced sarcopenia; Mitochondria; Mitophagy; Nicotinamide mononucleotide; Rab9
    DOI:  https://doi.org/10.1016/j.exger.2025.112970
  19. Cancer Res Commun. 2025 Nov 24.
    MicroCT enables simultaneous longitudinal tracking of murine pancreatic cancer progression and cachexia.
    Katherine R Pelz, Philip Jimenez, Colin J Daniel, Samuel D Newton, Melissa Cunningham, Rosalie C Sears, Patrick J Worth, Jonathan R Brody, Teresa A Zimmers.
      Preclinical models of pancreatic ductal adenocarcinoma (PDAC) can greatly benefit from noninvasive imaging for evaluating disease progression and therapeutic response. Imaging approaches that can accurately and simultaneously track primary tumor growth, metastatic dissemination, and host cachexia over time are lacking. Herein, we report an optimized dual-contrast micro-computed tomography (microCT) protocol for longitudinal imaging in orthotopic murine models of PDAC. This method enables high-resolution, volumetric quantification of orthotopic primary tumors, liver and lung metastases, and paraspinal skeletal muscle, providing a dynamic view of both the tumor and host physiology. MicroCT primary tumor measurements were strongly correlated with endpoint tumor weights and outperformed 2D ultrasound in early detection and volumetric accuracy, particularly for small or irregularly shaped tumors. This platform revealed heterogeneous metastatic kinetics across PDAC models and uncovered an early, heterogeneous onset of skeletal muscle wasting, a hallmark of cancer cachexia. Notably, this protocol mimics clinical CT surveillance by enabling opportunistic cachexia assessment from tumor imaging datasets, and offers substantial advantages over destructive endpoint analyses. Furthermore, microCT radiation dose had no effect on model endpoints. By capturing the temporal dynamics of tumor progression and host response, dual-contrast microCT serves as a powerful translational platform for preclinical PDAC research and therapeutic testing.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0414
  20. bioRxiv. 2025 Oct 29. pii: 2025.10.27.684882. [Epub ahead of print]
    Neuronal compartmentalization results in "impoverished" axonal mitochondria.
    Adrian Marti Pastor, Liam S C Lewis, Stephan Müller, Pedro Guedes-Dias, Lorena Olifiers, Polina Pelkonen, Almudena Del Rio Martin, Caroline Fecher, Nikolai P Skiba, Ying Hao, Antoneta Gavoci, Laura Trovo, Mehmet Akif Aktas, Hariharan M Mahadevan, Angelika B Harbauer, Howard M Bomze, Vadim Y Arshavsky, Monika S Brill, Romain Cartoni, Stefan F Lichtenthaler, Sidney M Gospe, Thomas Misgeld.
      Mitochondria differ depending on their location within a neuron. Morphological heterogeneity between somatic, dendritic, and axonal mitochondria is well established. Emerging evidence suggests that further specialization is needed to meet the unique demands of different neuronal compartments. However, the molecular and functional diversity of mitochondria within a neuron remains poorly understood. Here, we utilized proteomics in MitoTag mice to profile somatodendritic and axonal mitochondria across four distinct neuron types, thereby generating a compendium of intracellular mitochondrial diversity. Combining proteomics, functional, and immunofluorescence analyses, we demonstrated that axonal mitochondria are not defined by the presence of unique proteins, but rather by the selective loss or preservation of specific pathways compared to their somatodendritic counterparts. This results in "impoverished" axonal mitochondria, which are characterized by diminished mtDNA expression and impaired oxidative phosphorylation yet retain other pathways, such as fatty acid metabolism. Bioinformatic analyses of multiomic data identified local translation as one mechanism underlying compartment-specific diversity. Together, these findings provide a comprehensive in vivo framework for understanding mitochondrial specialization across neuronal compartments.
    DOI:  https://doi.org/10.1101/2025.10.27.684882
  21. Neurotherapeutics. 2025 Nov 25. pii: S1878-7479(25)00284-3. [Epub ahead of print] e00806
    A 16-amino acid peptide delays the progression of motor neuron degeneration and pathogenic symptoms in ALS models.
    Cheng-Yung Lin, Bing-Chang Lee, Po-Hsiang Zhang, Shao-Chi Lu, Wei-Zen Chang, Chia-Chuan Wang, Huai-Jen Tsai.
      Amyotrophic lateral sclerosis (ALS) is a progressive motor neurons (MNs) degenerative disease. Despite advancements in understanding ALS pathogenesis, drug development lags far behind. The reduced secretion of phosphoglycerate kinase 1 (Pgk1) by NogoA-overexpressing muscle cells inhibits neurite outgrowth of MNs (NOMNs). However, administration of extracellular Pgk1 (ePgk1) reduces phospho-Cofilin (p-Cofilin), a growth cone collapse marker, and mitigates MN degeneration. This improves NOMNs in NSC34 neural cells and locomotion in SOD1-G93A ALS-mice by suppressing the p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 signaling pathway. Here, we identified two Pgk1-based 16-amino acid (aa) short peptides, FD-1 and FD-2, with neuroprotective effects equivalent to those of full-length ePgk1. Administration of FD-1 or FD-2 (FD-1/-2) reduced p-Cofilin and promoted NOMNs in NSC34 ​cells cultured in conditioned medium obtained from NogoA-overexpressing muscle cells. Furthermore, we found that exogenous addition of FD-1/-2 to the culture medium attenuated the accumulation of phospho-Tau-S396 and the cytoplasmic mislocalization of transactive response DNA binding protein of 43 ​kDa (TDP-43) in oxidative-stressed ALS-like SOD1-G93A NSC34 ​cells. In FD-1/-2-injected zebrafish embryos, we observed increased caudal primary MNs branching. In C9orf72-knockdown and hTDP-43-G348C mRNA overexpressing zebrafish embryos injected with FD-1/-2, axonal growth and motor function were rescued. Moreover, intravenous injection of FD-1/-2 in SOD1-G93A ALS-mice delayed denervation of neuromuscular junction, preserved cell bodies of MNs in the ventral horn of spinal cord, increased grip strength, improved locomotion and prolonged survival. Therefore, both 16-aa short FD peptides are functionally equivalent to full-length 417-aa ePgk1 and thus promising therapeutic short peptides for the treatment of ALS.
    Keywords:  Amyotrophic lateral sclerosis; Motor neuron; Phosphoglycerate kinase 1; SOD1-G93A mice; Zebrafish
    DOI:  https://doi.org/10.1016/j.neurot.2025.e00806
  22. Sci Rep. 2025 Nov 26.
    Disulfiram inhibits Gasdermin D pores formation and improves insulin-dependent glucose uptake and glucose homeostasis in skeletal muscle of obesity-induced insulin-resistant mice.
    Cynthia Cadagan, Javier Russell-Guzmán, Luan Américo-Da-Silva, Paula Montaña, Genaro Barrientos, Sonja Buvinic, Gladys Tapia, Manuel Estrada, Paola Llanos.
      Insulin resistance (IR), which involves impaired insulin signaling diminished insulin sensitivity in skeletal muscle, is closely associated with chronic low-grade inflammation. A key mediator of this process is the NLRP3 inflammasome, which activates Gasdermin D (GSDMD). Upon cleavage, the N-terminal fragment of GSDMD (GSDMD-NT) forms membrane pores that facilitate interleukin-1β (IL-1β) release. Disulfiram (DSF), an FDA-approved drug that also inhibits GSDMD-NT pore formation, has emerged as a potential therapeutic for inflammasome-mediated inflammation. However, the role of GSDMD in skeletal muscle during IR remains poorly understood. This study evaluated whether GSDMD-NT-mediated IL-1β release contributes to skeletal muscle inflammation and IR, and whether DSF can restore insulin sensitivity. Male C57BL/6 mice were fed a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks; a subgroup of HFD-fed mice received intraperitoneal DSF (50 mg/kg) for 3 weeks. The flexor digitorum brevis (FDB) and gastrocnemius muscles were collected for single-fiber isolation, quantitative PCR, immunoblotting, and immunofluorescence. IL-1β levels were measured by ELISA. Insulin sensitivity was assessed via 2-NBDG uptake, Akt phosphorylation, and glucose tolerance tests (IPGTT). HFD-fed mice exhibited increased GSDMD-NT and oligomer levels, localized to the sarcolemma and T-tubules, along with elevated IL-1β in skeletal muscle. DSF administration reduced weight gain, fasting glycemia, IPGTT, and systemic IL-1β, while enhancing insulin-stimulated 2-NBDG uptake and Akt phosphorylation in FDB. Moreover, DSF reduced GSDMD-NT oligomerization and IL-1β release in the gastrocnemius muscle. These findings suggest a novel pathogenic role for GSDMD in skeletal muscle IR and support DSF as a potential candidate for metabolic disease intervention.
    Keywords:  GSDMD-NT; Glucose uptake; IL-1β release; Insulin signaling; NALP3 inflammasome
    DOI:  https://doi.org/10.1038/s41598-025-30058-6
  23. Int J Mol Sci. 2025 Nov 13. pii: 10977. [Epub ahead of print]26(22):
    Targeting TOMM40 and TOMM22 to Rescue Statin-Impaired Mitochondrial Function, Dynamics, and Mitophagy in Skeletal Myotubes.
    Neil V Yang, Sean Rogers, Rachel Guerra, Justin Y Chao, David J Pagliarini, Elizabeth Theusch, Ronald M Krauss.
      Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well-tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated in the development of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates the transcription of TOMM40 and TOMM22, genes that encode major subunits of the translocase of the outer mitochondrial membrane (TOM) complex. Mitochondrial effects of knockdown of TOMM40 and TOMM22 in mouse C2C12 and primary human skeletal cell myotubes include impaired oxidative function, increased superoxide production, reduced cholesterol and CoQ levels, and disrupted markers of mitochondrial dynamics and morphology as well as increased mitophagy, with similar effects resulting from simvastatin exposure. Overexpression of TOMM40 and TOMM22 in simvastatin-treated mouse and human skeletal muscle cells rescued effects on markers of mitochondrial dynamics and morphology, but not oxidative function or cholesterol and CoQ levels. These results show that TOMM40 and TOMM22 have key roles in maintaining both mitochondrial dynamics and function and indicate that their downregulation by statin treatment results in mitochondrial effects that may contribute to statin-induced myopathy.
    Keywords:  mitochondrial dynamics; skeletal muscle; statin; translocase of outer mitochondrial membrane; transmission electron microscopy
    DOI:  https://doi.org/10.3390/ijms262210977
  24. Mol Immunol. 2025 Nov 21. pii: S0161-5890(25)00264-0. [Epub ahead of print]188 142-153
    Association of YY1 with STING activation and the inflammatory response during early muscle injury repair.
    Xili Yan, Zhongxing Hou, Wenxin Li, Shuang Miao, Zejia Zhang, Jie Luo, Yinan Tao, Qiang Li, Jian Zhao, Zhiliang Xu.
       BACKGROUND: Skeletal muscle injury is a common sports injury. Although the cGAS-STING signaling pathway is implicated in myoblast differentiation and muscle regeneration, its precise mechanisms remain unclear. Yin Yang 1 (YY1), a multifunctional transcriptional and chromatin regulator involved in various pathologies, also requires investigation for its specific role in regeneration.
    OBJECTIVES: This study aimed to investigate the association between YY1 and cGAS-STING pathway activation during early muscle regeneration, and explore its potential role in the inflammatory phase of myoblast differentiation.
    METHODS: A skeletal muscle injury model was established in C57BL/6 mice using 1.2 % barium chloride. H&E staining evaluated muscle regeneration. Immunohistochemistry (IHC) quantified MyoG, YY1, H2Bub, and RNF20 expression. Immunofluorescence (IF) determined STING and YY1 expression. Western blotting measured cGAS, STING, YY1, caspase-3, IRF3, P-IRF3,P-TBK1, H2Bub and RNF20 protein levels. qPCR analyzed mRNA of inflammatory factors (IL-6, IL-17, IL-1β, TNF-α), myogenic regulators (MyoD, MyoG, Myf5), and signaling molecules (cGAS, STING, YY1, IRF3, caspase-3). Co-immunoprecipitation (Co-IP) assessed STING-YY1 interaction.
    RESULTS: Post-injury histology revealed significant pathology and inflammation. qPCR indicated upregulated mRNA levels of inflammatory factors and myogenic/signaling molecules at day 3, with partial recovery by day 7. Consistently, IHC (YY1, H2Bub, RNF20), IF (STING, YY1), and WB (cGAS, STING, YY1, caspase-3, IRF3, P-IRF3,P-TBK1, H2Bub and RNF20) all demonstrated elevated expression at day 3, declining by day 7. Co-IP confirmed a direct STING-YY1 interaction.
    CONCLUSION: Our findings reveal a significant association between YY1 and cGAS-STING signaling activation, suggesting that this interplay contributes to the modulation of the inflammatory response during the early phase of skeletal muscle repair.
    Keywords:  Inflammatory response; STING; Skeletal muscle injury; YY1; cGAS
    DOI:  https://doi.org/10.1016/j.molimm.2025.11.011
  25. bioRxiv. 2025 Nov 14. pii: 2025.11.13.687882. [Epub ahead of print]
    Fiber Type and Stimulus Determine Progression of Skeletal Muscle Atrophy.
    Gregory L Maas, Marcus P Mullen, Brooke D Shepard, Jack F Gugel, Dakota R Hunt, Virginia Ferguson, Sarah Calve, Thomas G Martin, Leslie A Leinwand.
       Background: Skeletal muscle atrophy is prevalent worldwide and is a major detractor from length and quality of life. It is often diagnosed and treated as a single disorder, but the causal stimuli and progression of atrophy vary widely. Malnutrition and disuse are two common causes of muscle atrophy, and despite their prevalence and extensive characterization, there have been no direct comparisons of how these two types of atrophy progress and whether they differentially affect skeletal muscle fiber types. The purpose of this study is to directly compare atrophy from fasting and disuse and provide a transcriptomic resource for future research on both conditions.
    Methods: We fasted or hindlimb suspended (HS) two cohorts of 12-week-old female C57/bl6 mice. Mice were fasted for up to 72 hours to induce malnutrition atrophy or were hindlimb suspended for 0, 3, 7, 14, or 28 days to induce disuse atrophy. At each timepoint, mice were euthanized and three muscles (tibialis anterior (TA), extensor digitorum longus (EDL), and soleus) were weighed and collected for RNA sequencing. Atrophy progression and gene expression changes were compared across muscle fiber types and atrophy stimuli.
    Results: We found differences in atrophy progression between muscle fiber types based on fiber twitch speed and atrophy stimulus. Fasted mice lost 25% of their body weight and 23% of fast-twitch TA mass with little change in soleus. In contrast, HS mice lost 40% of the slower-twitch soleus but the effect on the TA was negligible. Gene expression varied in response to both atrophy stimuli, but a greater number of genes changed with fasting compared to HS in the EDL and soleus. By muscle type, a greater transcriptional shift occurred in the EDL with fasting while the soleus showed more gene changes during HS. Enrichment analysis of transcriptional changes showed similarities (downregulation in muscle growth pathways) and differences (increased fatty acid metabolism in fasting and increased neuronal activity in HS) between atrophy stimuli.
    Conclusions: Atrophy progression varies based on stimuli and muscle fiber type. This study provides a large, matched data set where the effects of different atrophic stimuli can be easily and directly compared in multiple fiber types. To our knowledge, this is the first study to closely compare these two atrophy stimuli in a muscle type-specific context. This work demonstrates that atrophy is not a single disorder and that the development of therapies may need to be tailored to the atrophic stimulus.
    DOI:  https://doi.org/10.1101/2025.11.13.687882
  26. bioRxiv. 2025 Nov 06. pii: 2025.11.06.686916. [Epub ahead of print]
    Hypoxia-induced mitoROS triggers M1 linear ubiquitin chains and activates NF-κB signaling.
    Kiri Tal, Jonathan Ram, Reis Noa, Maniv Inbal, Ordureau Alban, Michael H Glickman, Sulkshane Prasad.
      Mitochondria are essential organelles responsible for cellular energy production and metabolism. Hypoxia, a pathophysiological condition, impairs the electron transport chain, disrupts mitochondrial function, and produces harmful reactive oxygen species (ROS). Ubiquitin signaling regulates mitochondrial health through several mechanisms, including protein degradation and mitophagy. Here, we show that hypoxia-induced mitophagy occurs independently of ubiquitination. However, mitochondria are heavily ubiquitinated under hypoxic stress. A significant portion of these hypoxia-induced ubiquitin chains constitute a specific type: linear head-to-tail fusions (M1), which are known for their role in NF-κB activation during cytokine signaling. We demonstrate that hypoxia-induced mitochondrial ROS leads to the accumulation of these M1 chains, activating NF-κB signaling and increasing the expression of its target genes. These findings reveal a critical internal signal that helps cells adapt to mitochondrial stress and triggers an inflammatory response.
    DOI:  https://doi.org/10.1101/2025.11.06.686916
  27. Proc Natl Acad Sci U S A. 2025 Dec 02. 122(48): e2511539122
    The lysosomal carrier SLC29A3 supports antibacterial signaling, and promotes autophagy by activating TRPML1 in murine dendritic cells.
    Daniel J Netting, Cynthia López-Haber, Zachary Hutchins, José A Martina, Rosa Puertollano, Adriana R Mantegazza.
      The solute carrier (SLC)29A3 exports nucleosides from lysosomes into the cytosol, maintaining solute homeostasis and providing metabolic intermediates for cellular processes. Loss-of-function mutations in SLC29A3 cause H syndrome, characterized by histiocytosis, hyperinflammation, and immunodeficiency. While dysfunctions in various cell types contribute to H syndrome and to SLC29A3 deficiency in mice, the mechanisms driving hyperinflammation and immunodeficiency are incompletely understood. Remarkably, the possible role played by dendritic cells (DCs), the most efficient antigen (Ag)-presenting cells and the main cellular link between innate and adaptive immunity, remains unknown. We show that, in murine DCs, SLC29A3 is recruited to phagosomes after bacterial capture, maintains phagosomal pH homeostasis, and ensures optimal antimicrobial phagosomal signaling to the production of IL-6, IL-12, pro-IL-1β, and CCL22. In addition, SLC29A3 promotes Ag presentation on MHC-II molecules to initiate adaptive immune responses. Notably, SLC29A3 supports the activity of the lysosomal calcium channel TRPML1, promoting the nuclear translocation of transcription factor TFEB and inducing autophagy, a major anti-inflammatory mechanism. Overexpression of human SLC29A3, but not the transport mutant G437R, in SLC29A3-deficient murine DCs restores cytokine production in response to bacterial phagocytosis, suggesting that SLC29A3 transport activity is required to drive phagosomal signaling. Our data suggest that SLC29A3 supports and controls immune function in DCs by promoting effective antimicrobial signaling and Ag presentation, and inducing autophagy. Our findings also uncover a TRPML1-dependent mechanism by which SLC29A3 activates TFEB and suggest that defects in phagosomal antibacterial signaling, TFEB activation, and autophagy may contribute to immunodeficiency and hyperinflammation in SLC29A3 disorders.
    Keywords:  TFEB; antigen MHC-II presentation; autophagy; dendritic cells; lysosomal solute carriers
    DOI:  https://doi.org/10.1073/pnas.2511539122
  28. Int J Mol Sci. 2025 Nov 13. pii: 10985. [Epub ahead of print]26(22):
    Multiple Defects in Muscle Regeneration in the HSALR Mouse Model of RNA Toxicity.
    Ramesh S Yadava, Mira A Zineddin, Mani S Mahadevan.
      Myotonic dystrophy type 1 (DM1) results from the toxicity of RNA produced from the mutant allele of the DMPK gene. The mechanism by which the toxic RNA causes muscular dystrophy in DM1 is unknown. Dystrophy in DM1 is associated with defective muscle regeneration and repair. Here, we used the BaCl2-induced damage model of muscle injury to study muscle regeneration in the HSALR mouse model of DM1. We have previously shown delayed muscle regeneration and deleterious effects on satellite cell numbers in another mouse model of RNA toxicity using similar experimental approaches. We found that HSALR mice show no apparent deleterious effects on satellite cell number or early markers of muscle regeneration. Further analysis at later time points after damage showed increased numbers of internal nuclei as compared to control mice undergoing the same protocol. Muscle fiber type analysis using immunostaining for type IIA and IIB fibers identified a switch to slower fibers (increased fraction of IIA and reduced fraction of IIB fibers) after regeneration in HSALR mice as compared to regenerated muscle from wildtype mice.
    Keywords:  RNA toxicity; fiber type; muscle regeneration; muscular dystrophy; myotonic dystrophy; satellite cells
    DOI:  https://doi.org/10.3390/ijms262210985
  29. Sci Rep. 2025 Nov 28.
    RAGE contributes to persistent sepsis-induced muscle and mitochondrial alterations.
    Raphaël Romien, Alexandre Pierre, Sarah Ducastel, Arthur Dubech, Jérémy Lemaire, Gaëlle Grolaux, Marie Frimat, Benoit Brassart, Claire Bourel, Michael Howsam, Cécile Yelnik, Eric Boulanger, Raphaël Favory, Sebastien Preau, Steve Lancel.
      A majority of patients surviving sepsis develop muscle weakness. However, the underlying cellular and molecular pathways remain largely unexplored. To determine whether sepsis leads to long-term persistent muscular consequences and to identify the underlying mechanisms, we used a murine model of reanimated sepsis induced by intraperitoneal injection of a heterologous stool slurry. Muscles were analyzed 3 months later. The oxidative muscle exhibited reduced fatigue resistance and decreased mitochondrial respiration, without a corresponding reduction in mitochondrial OXPHOS proteins. Glycolytic and mixed muscle fibres were atrophied. Markers of oxidative and mitochondrial stress, as well as genes involved in mitochondrial fission, remained present 3 months after sepsis. Low-grade, but significant, muscular inflammation was also measured. Specifically, both the NLRP3 inflammasome and the receptor of Advanced Glycation End-products (RAGE) axis were upregulated. Interestingly, long-term sepsis-induced muscular consequences were not observed in RAGE knockout mice. Overall, we describe for the first time in mice that sepsis causes long-lasting muscle dysfunction after recovery, including mitochondrial alterations and low-grade inflammation, and that RAGE may represent a promising target to mitigate long-term muscle alterations induced by sepsis.
    DOI:  https://doi.org/10.1038/s41598-025-28645-8
  30. Nat Commun. 2025 Nov 24. 16(1): 10395
    Single-nucleus and spatial transcriptomic profiling of human temporal cortex and white matter reveals key associations with AD pathology.
    Pallavi Gaur, Julien Bryois, Daniela Calini, Lynette C Foo, Jeroen J M Hoozemans, Archana Yadav, Dheeraj Malhotra, Vilas Menon.
      Alzheimer's disease, the leading cause of dementia in the elderly, is a neurodegenerative disorder that has been studied to uncover therapeutic pathways through its molecular and cellular hallmarks. Here, we present a comprehensive investigation of cellular heterogeneity from the temporal cortex region of 40 individuals, comprising healthy donors and individuals with differing AD pathology. Using single-nucleus transcriptomic analysis of 430,271 nuclei from both gray and white matter of these individuals, we identified cell type-specific subclusters in both neuronal and glial cell types with varying degrees of association with AD pathology. We extended this analysis by performing multiplexed in situ hybridization using the CARTANA platform, capturing 155 genes in 13 individuals with differing tau pathology. We not only replicated snRNA data key findings from our spatial data analysis but also identified a set of cell type-specific genes that show selective enrichment or depletion near pathological inclusions.
    DOI:  https://doi.org/10.1038/s41467-025-65350-6
  31. Med. 2025 Nov 21. pii: S2666-6340(25)00355-1. [Epub ahead of print] 100928
    IsomiR utility in amyotrophic lateral sclerosis prognostication.
    Yahel Cohen, Ilan Sinai, Iddo Magen, Yehuda Matan Danino, Joanne Wuu, Andrea Malaspina, Michael Benatar, Eran Hornstein.
       BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. IsomiRs are microRNA (miRNA) isoforms that arise from alternative processing or editing events during miRNA biogenesis. While isomiRs may carry distinct biological and clinical relevance, their potential as cell-free biomarkers in neurodegeneration remains largely unexplored.
    METHODS: Here, we investigated the prognostic utility of plasma isomiRs in ALS, using next-generation sequencing and two orthogonal statistical approaches.
    FINDINGS: We profiled cell-free isomiRs in 154 ALS patients from a British cohort and identified higher levels of one isomiR, let-7g-5p.t, to be associated with longer survival. This finding was independently validated in an international ALS cohort of 200 patients. let-7g-5p.t prognostic utility was comparable to that of neurofilament light chain (NfL) or miR-181.
    CONCLUSIONS: These results establish isomiRs as a novel class of blood-based biomarkers in ALS with the potential to refine prognostication in clinical trials for neurodegenerative diseases.
    FUNDING: This study was funded by Target ALS the Israel Science Foundation (3497/21, 424/22) and the CReATe Consortium. All additional funding can be found under the Acknowledgments.
    Keywords:  amyotrophic lateral sclerosis; isomiRs; machine learning in biomedicine; miRNA; neurodegenerative diseases; prognostic biomarkers; small RNA biomarkers; survival analysis; translation to patients; translational neuroscience
    DOI:  https://doi.org/10.1016/j.medj.2025.100928
  32. Antioxidants (Basel). 2025 Oct 24. pii: 1276. [Epub ahead of print]14(11):
    cGAS-STING-NF-κB Axis Mediates Rotenone-Induced NLRP3 Inflammasome Activation Through Mitochondrial DNA Release.
    Yewon Mun, Juseo Kim, You-Jin Choi, Byung-Hoon Lee.
      Rotenone, a classical inhibitor of mitochondrial complex I, disrupts electron transport and promotes the generation of reactive oxygen species (ROS), contributing to inflammation and cell death. However, the precise molecular mechanisms linking mitochondrial dysfunction to inflammatory signaling remain incompletely understood. In this study, we investigated the role of the cGAS-STING pathway in rotenone-induced NLRP3 inflammasome activation in PMA-differentiated THP-1 macrophages. Rotenone treatment activated the cGAS-STING axis, as evidenced by increased cGAS expression and the phosphorylation of STING and TBK1. This activation led to the nuclear translocation of NF-κB and the upregulation of NLRP3, promoting inflammasome priming and IL-1β secretion. Inhibition of STING using H-151 markedly suppressed NLRP3 expression, NF-κB activation, and IL-1β release. Similarly, cyclosporin A, an inhibitor of mitochondrial permeability transition pore opening, reduced mitochondrial ROS, cytosolic oxidized mitochondrial DNA, and downstream activation of the cGAS-STING pathway, thereby attenuating inflammasome activation. These findings demonstrate that rotenone activates the NLRP3 inflammasome via mitochondrial ROS-mediated release of mtDNA and subsequent activation of the cGAS-STING-NF-κB signaling axis in THP-1-derived macrophages.
    Keywords:  NF-κB; NLRP3 inflammasome; cGAS–STING pathway; mitochondrial DNA; rotenone
    DOI:  https://doi.org/10.3390/antiox14111276
  33. Geroscience. 2025 Nov 22.
    Nicotinamide riboside supplementation restores microglial health and improves cognition in aged male mice.
    Ramkumar Thiyagarajan, Rupadevi Muthaiah, Bhavana Sreevelu, Owen P Treanor, Yonas Redae, Reem Berman, Anna L Davis, Nanda Yellapu, Spencer R Rosario, Lee D Chaves, Kenneth L Seldeen, Bruce R Troen.
      Cognitive impairment affects 1 in 6 individuals over 60, with over 75 million projected by 2030. Age-related changes in microglial function and declining nicotinamide adenine dinucleotide (NAD+) levels may contribute to cognitive decline. Although nicotinamide riboside (NR) supplementation can restore NAD+ levels in aged mice, its effects on microglial phenotype and cognition during normal aging remain unclear. We assessed cognitive function, neuroinflammation, and microglial gene expression in 6-month (Young) and 22-month (Aged) mice, along with aged mice supplemented with NR (Aged + NR; 400 mg/kg body weight) for 8 weeks. Aged mice exhibited impaired cognition and increased gene expression related to neuroinflammation. NR supplementation improved or prevented the decline in nest-building ability, Y-maze spontaneous alternation, and novel object recognition, which are reflective of instrumental activities of daily living, spatial working memory, and recognition memory. NR supplementation diminished microglial (IBA1) and astrocytic (GFAP) activation, resembling the young phenotype. Gene expression profiling revealed reduced microglial activation, inflammatory pathways, and chemokine production in Aged + NR mice, along with upregulation of genes associated with learning, memory, and gliogenesis. NR lowered transcriptional signatures from age-dependent (ADEM) and disease-associated (DAM) microglia and enhanced homeostatic state profiles. Metabolic pathway analysis of microglial transcripts indicated that NR suppressed age-induced increases in fatty acid metabolism. This was supported by immunostaining, which showed reduced lipoprotein lipase (LPL), a DAM marker, in the cortex and hippocampus. Overall, NR appeared to mitigate age-related cognitive decline by shifting microglial gene expression and metabolism toward a younger phenotype, suggesting potential therapeutic relevance for healthy brain aging.
    Keywords:  Aging; Cognition decline; Disease-associated microglia; Microglia; NAD metabolism
    DOI:  https://doi.org/10.1007/s11357-025-01959-1
  34. bioRxiv. 2025 Oct 23. pii: 2025.10.21.683798. [Epub ahead of print]
    Inhibition of Mitochondrial Complex III Causes Dopaminergic Neurodegeneration by Redox Stress in Caenorhabditis elegans.
    Javier Huayta, Joel N Meyer.
      Environmental factors including chemical exposures are important contributors to Parkinson's disease (PD). Nearly all well-validated chemicals involved in PD affect mitochondria, and the great majority of those identified inhibit mitochondrial complex I, causing ATP depletion and oxidative stress. We hypothesized that inhibition of mitochondrial complex III would also cause dopaminergic neurodegeneration. Using Caenorhabditis elegans to evaluate the in vivo effects of the complex III-inhibiting pesticides antimycin A and pyraclostrobin, we found that both caused neurodegeneration. Neurodegeneration was specific to the dopamine neurons, and complex III inhibition caused a more-oxidized cellular environment in those neurons. Pharmacological and genetic antioxidant interventions rescued neurodegeneration, but energetic rescue attempts did not. Finally, optogenetic production of superoxide anion specifically at complex III caused dopaminergic neurodegeneration. Thus, redox stress at complex III is sufficient for dopaminergic neurodegeneration, and redox stress following chemical inhibition is necessary for dopaminergic neurodegeneration in vivo in C. elegans.
    DOI:  https://doi.org/10.1101/2025.10.21.683798
  35. bioRxiv. 2025 Oct 07. pii: 2025.10.06.680736. [Epub ahead of print]
    Age- and Sex- Driven Transcriptional and Metabolic Diversity in Myeloid-Derived Suppressor Cells After Mouse Sepsis.
    Christine Rodhouse, Dayuan Wang, Hongru Tang, Valerie E Polcz, Miguel Hernández-Ríos, Xuanxuan Yu, Leandro Balzano-Nogueira, Jaimar C Rincon, Angel Charles, Seiichiro Fujishima, Quan Vo, Marvin L Dirain, Ricardo Ungaro, Dina C Nacionales, Leilani Zeumer-Spataro, Larissa Langhi Prata, Shawn D Larson, Gemma Casadesus, Feifei Xiao, Shannon M Wallet, Maigan A Brusko, Tyler J Loftus, Letitia Bible, Alicia M Mohr, Paramita Chakrabarty, Michael P Kladde, Clayton E Mathews, Lyle L Moldawer, Robert Maile, Guoshuai Cai, Philip A Efron.
      Sepsis induces profound immune dysregulation, often resulting in chronic critical illness characterized by persistent immunosuppression and poor outcomes. Myeloid-derived suppressor cells (MDSCs) are central mediators of this immunosuppressive phenotype, yet the influence of age and sex on their transcriptional and metabolic states remain poorly understood. Here, we employed single-cell RNA sequencing of splenic leukocytes from young (3-4 months) and older (18-24 months) adult male and female mice subjected to a clinically relevant murine sepsis model to define age- and sex-specific MDSC phenotypes. We identified significant differences regarding age and sex in MDSC expansion, transcriptome, canonical pathway activation, RNA velocity, mitochondrial metabolism, and predicted cell-cell communication after sepsis. Using drug2cell analysis of total leukocytes we also identified cohort-specific drug target profiles. These findings underscore the importance of age and sex in shaping sepsis-induced MDSC biology and suggest that personalized immunomodulatory strategies targeting MDSCs could improve sepsis outcomes.
    Keywords:  myeloid-derived suppressor cells; precision medicine; sepsis
    DOI:  https://doi.org/10.1101/2025.10.06.680736
  36. Nat Commun. 2025 Nov 28. 16(1): 10761
    Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.
    Candice Kutchukian, Maria Casas, Rose E Dixon, Eamonn J Dickson.
      Lysosomes are essential organelles that regulate cellular homeostasis through complex membrane interactions. Phosphoinositide lipids play critical roles in orchestrating these functions by recruiting specific proteins to organelle membranes. The PIKfyve/Fig4/Vac14 complex regulates PI(3,5)P₂ metabolism, and intriguingly, while loss-of-function mutations cause neurodegeneration, acute PIKfyve inhibition shows therapeutic potential in neurodegenerative disorders. We demonstrate that PIKfyve/Fig4/Vac14 dysfunction triggers a compensatory response where reduced mTORC1 activity leads to ULK1-dependent trafficking of ATG9A and PI4KIIα from the TGN to lysosomes. This increases lysosomal PI(4)P, facilitating cholesterol and phosphatidylserine transport at ER-lysosome contacts to promote membrane repair. Concurrently, elevated lysosomal PI(4)P recruits ORP1L to ER-lysosome-mitochondria three-way contacts, enabling PI(4)P transfer to mitochondria that drives ULK1-dependent fragmentation and increased respiration. These findings reveal a role for PIKfyve/Fig4/Vac14 in coordinating lysosomal repair and mitochondrial homeostasis, offering insights into cellular stress responses.
    DOI:  https://doi.org/10.1038/s41467-025-65798-6
  37. iScience. 2025 Nov 21. 28(11): 113853
    ATP6V0D2 drives triple-negative breast cancer progression and inhibits cisplatin sensitivity by promoting PHLPP2 lysosomal degradation.
    Jingyu Zhang, Congbo Cao, Hongyu Yang, Liu Yang, Meiqi Wang, Xiaohan Liu, Xin Hao, Yuanyuan Zhang, Xiaohan Wang, Zhenchuan Song.
      Triple-negative breast cancer (TNBC) faces therapeutic challenges due to limited treatment options and frequent chemoresistance. In this study, we identify ATP6V0D2 as a key factor upregulated in TNBC, where its expression correlates with poor prognosis. Transcriptomic and functional analyses linked ATP6V0D2 to PI3K/AKT signaling and platinum drug resistance. Mechanistically, ATP6V0D2 enhanced lysosomal function to promote degradation of the tumor suppressor PHLPP2, thereby sustaining AKT phosphorylation. Functional assays showed that ATP6V0D2 knockdown increased cisplatin sensitivity both in vitro and in vivo. Furthermore, pharmacological inhibition of V-ATPase with bafilomycinA1 sensitized TNBC patient-derived organoids to cisplatin. Clinically, our analysis of 91 TNBC patients who received cisplatin-based neoadjuvant chemotherapy found that high ATP6V0D2 expression was inversely correlated with pathological complete response (pCR), whereas PHLPP2 levels showed positive association, supporting the proposed mechanistic link. Together, these findings highlight the impact of ATP6V0D2 on TNBC progression and cisplatin sensitivity, nominating ATP6V0D2 as a promising therapeutic target.
    Keywords:  Cancer; Target identification; Therapeutics
    DOI:  https://doi.org/10.1016/j.isci.2025.113853
  38. bioRxiv. 2025 Nov 02. pii: 2025.10.31.685813. [Epub ahead of print]
    KIF5A binds RNA to orchestrate synaptic mRNA localization and stress granules in ALS.
    Phuong Le, Neeraj K Lal, Shuhao Xu, Sara Mumford, Megan Huang, Dong Yang, Orel Mizrahi, Benjamin Hoover, Brian Yee, Yuan Mei, Katherine Rothamel, Hsuan-Lin Her, Steven M Blue, Neil A Shneider, Gene W Yeo.
      Neuronal health depends on the precise transport and local translation of mRNAs to maintain synaptic function across highly polarized cellular architecture. While kinesin motor proteins are known to mediate mRNA transport, the specificity and direct involvement of individual kinesins as RNA-binding proteins (RBPs) remain unclear. Here, we demonstrate that KIF5A, a neuron-specific kinesin implicated in amyotrophic lateral sclerosis (ALS), functions as an RBP. We show that KIF5A directly binds mRNAs encoding synaptic ribosomal proteins and is required for their synaptic localization and for maintaining normal synaptic composition and function. Additionally, we show ALS-linked KIF5A mutations confer gain-of-function properties, enhancing mRNA binding, increasing synaptic ribosomal protein accumulation, inducing neuronal hyperexcitability, and impairing stress responses. These findings reveal a previously unrecognized mechanism by which mutant KIF5A disrupts synaptic homeostasis. Our work positions a kinesin motor protein as an RBP with critical roles in mRNA transport, local translation, and stress response.
    Highlights: KIF5A interacts with mRNA encoding synaptic ribosomal proteinsKIF5A is required for normal synaptic composition and functionKIF5A binds to G3BP1 and G3BP1 stress granule associated proteinsKIF5A mutant ALS patient-derived motor neurons have abnormal synaptic function and stress response.
    DOI:  https://doi.org/10.1101/2025.10.31.685813
  39. bioRxiv. 2025 Nov 06. pii: 2025.11.04.686639. [Epub ahead of print]
    Disruption of the insulin signaling pathway in C. elegans dramatically increases male longevity and enhances reproductive health late in life.
    Rose S Al-Saadi, Hannah B Lewack, Patrick C Phillips.
      Males and females are known to have dramatically different health and lifespan trajectories, but the underlying basis for these differences is only now being fully investigated 1 . In the Caenorhabditis elegans nematode model system, most aging studies have been conducted with hermaphrodites, and little is known about male-specific responses to pro-longevity mutations. Several previous studies have used the auxin-inducible degron system to degrade the insulin-like DAF-2/IGF-1 receptor in hermaphrodites, finding that both ubiquitous and tissue-specific degradation can extend lifespan 2-4 . Here we show that ubiquitous degradation of DAF-2 in male C. elegans increases median lifespan by more than 440%, one of the longest lifespan extensions by a single intervention to date. Conversely, degrading DAF-2 in the male germline decreased lifespan, opposite of its effect in hermaphrodites 3 . Using male mating and reproductive success as a meaningful ecological and neurophysiological measure of healthspan, we found that ubiquitous degradation of DAF-2 greatly prolongs reproductive health, likely by prolonging function of the male intromittent organ in the tail. This work highlights the importance of studying sex differences in aging and highlights the utility of using C. elegans males to understand the underlying basis of enhanced lifespan and healthspan.
    DOI:  https://doi.org/10.1101/2025.11.04.686639
This page is being maintained by Thomas Krichel. It was last updated on 2025‒12‒22 at 11:55.