bims-musmir Biomed News
on microRNAs in muscle
Issue of 2025–11–16
eleven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway
  1. Impaired cAMP-PKA-CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia.
  2. Alterations in peroxisome-mitochondria interplay in skeletal muscle accelerate muscle dysfunction.
  3. STX4 Is Indispensable for Mitochondrial Homeostasis in Skeletal Muscle.
  4. Primary-Stage Colon Cancer Impairs Muscle Energy Metabolism by Suppressing Mitochondrial Complex I Activity.
  5. miRNA changes with ageing and caloric restriction in male rat skeletal muscle: potential roles in muscle cell function.
  6. Nutritional strategies against skeletal muscle wasting in cancer-associated cachexia: the role of β-hydroxybutyrate and polyunsaturated fatty acids.
  7. Advancements of investigational agents for cancer cachexia: what clinical progress have we seen in the last 5 years?
  8. Inhibition of NLRP3 inflammasome activation alleviated liver injury and wasting effect in tumor-bearing mice.
  9. Role of Peptides in Skeletal Muscle Wasting: A Scoping Review.
  10. Reawakening cAMP signalling in cancer cachexia.
  11. Novel missense variants associated with GNE myopathy.
  1. Nat Metab. 2025 Nov 12.
    Impaired cAMP-PKA-CREB1 signalling drives mitochondrial dysfunction in skeletal muscle during cancer cachexia.
    Elia Angelino, Lorenza Bodo, Roberta Sartori, Valeria Malacarne, Beatrice D'Anna, Nicolò Formaggio, Suvham Barua, Tommaso Raiteri, Andrea Lauria, Simone Reano, Alessandra Murabito, Monica Nicolau, Fabiana Ferrero, Camilla Pezzini, Giulia Rossino, Francesco Favero, Michele Valmasoni, Nicoletta Filigheddu, Alessio Menga, Davide Corà, Emilio Hirsch, Salvatore Oliviero, Vittorio Sartorelli, Valentina Proserpio, Alessandra Ghigo, Marco Sandri, Paolo E Porporato, Daniela Talarico, Giuseppina Caretti, Andrea Graziani.
      Skeletal muscle wasting is a defining feature of cancer cachexia, a multifactorial syndrome that drastically compromises patient quality of life and treatment outcomes. Mitochondrial dysfunction is a major contributor to skeletal muscle wasting in cancer cachexia, yet the upstream molecular drivers remain elusive. Here we show that cancer impairs the activity of cAMP-dependent protein kinase A (PKA) and of its transcriptional effector CREB1 in skeletal muscle, ultimately contributing to the downregulation of a core transcriptional network that supports mitochondrial integrity and function. The restoration of cAMP-PKA-CREB1 signalling through pharmacological inhibition of the cAMP-hydrolysing phosphodiesterase 4 (PDE4) rescues the expression of mitochondrial-related genes, improves mitochondrial function and mitigates skeletal muscle wasting in male mice. Altogether, our data identify tumour-induced suppression of the cAMP-PKA-CREB1 axis as a central mechanism contributing to mitochondrial dysfunction in skeletal muscle during cancer cachexia. Furthermore, these findings highlight PDE4, particularly the PDE4D isoform, as a potential therapeutic target to preserve muscle mitochondrial function and counteract muscle wasting in cancer cachexia.
    DOI:  https://doi.org/10.1038/s42255-025-01397-5
  2. Nat Commun. 2025 Nov 10. 16(1): 9868
    Alterations in peroxisome-mitochondria interplay in skeletal muscle accelerate muscle dysfunction.
    Marco Scalabrin, Eloisa Turco, Ilaria Davigo, Riccardo Filadi, Leonardo Nogara, Gaia Gherardi, Lucia Barazzuol, Andrea Armani, Giulia Trani, Samuele Negro, Anais Franco-Romero, Yorrick Jaspers, Elisa Baschiera, Rossella De Cegli, Eugenio Del Prete, Tito Cali, Bert Blaauw, Leonardo Salviati, Michela Rigoni, Cristina Mammucari, Sylvie Caspar-Bauguil, Cedric Moro, Paola Pizzo, Marco Sandri, Stephan Kemp, Vanina Romanello.
      Skeletal muscles, which constitute 40-50% of body mass, regulate whole-body energy expenditure and glucose and lipid metabolism. Peroxisomes are dynamic organelles that play a crucial role in lipid metabolism and clearance of reactive oxygen species, however their role in skeletal muscle remains poorly understood. To clarify this issue, we generated a muscle-specific transgenic mouse line with peroxisome import deficiency through the deletion of peroxisomal biogenesis factor 5 (Pex5). Here, we show that Pex5 inhibition results in impaired lipid metabolism, reduced muscle force and exercise performance. Moreover, mitochondrial structure, content, and function are also altered, accelerating the onset of age-related structural defects, neuromuscular junction degeneration, and muscle atrophy. Consistent with these observations, we observe a decline in peroxisomal content in the muscles of control mice undergoing natural aging. Altogether, our findings show the importance of preserving peroxisomal function and their interplay with mitochondria to maintain muscle health during aging.
    DOI:  https://doi.org/10.1038/s41467-025-64833-w
  3. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70113
    STX4 Is Indispensable for Mitochondrial Homeostasis in Skeletal Muscle.
    Joseph M Hoolachan, Rekha Balakrishnan, Erika M McCown, Karla E Merz, Chunxue Zhou, Elizabeth Bloom-Saldana, Patrick T Fueger, Angelica Hamilton, Tali Kiperman, Ke Ma, Eunjin Oh, Lei Jiang, Patrick Pirrotte, Orian Shirihai, Debbie C Thurmond.
       BACKGROUND: Mitochondrial homeostasis is vital for optimal skeletal muscle integrity. Mitochondrial quality control (MQC) mechanisms that are essential for maintaining proper functions of mitochondria include mitochondrial biogenesis, dynamics and mitophagy. Previously, Syntaxin 4 (STX4), traditionally considered a cell surface protein known for glucose uptake in skeletal muscle, was also identified at the outer mitochondrial membrane. STX4 enrichment was sufficient to reverse Type 2 diabetes-associated mitochondrial damage in skeletal muscle by inactivation of mitochondrial fission. However, whether STX4 could modulate skeletal muscle mitochondrial homeostasis through MQC mechanisms involving mitochondrial biogenesis or mitophagy remains to be determined.
    METHODS: To determine the requirements of STX4 in mitochondrial structure, function and MQC processes of biogenesis and mitophagy, we implemented our in-house generated inducible skeletal muscle-specific STX4-knockout (skmSTX4-iKO) mice (Stx4fl/fl; Tg (HSA-rtTA/TRE-Cre)/B6) and STX4-depleted immortalized L6.GLUT4myc myotubes via siRNA knockdown (siSTX4).
    RESULTS: We found that non-obese skmSTX4-iKO male mice (> 50% reduced STX4 abundance, soleus and gastrocnemius ***p < 0.001, tibialis anterior (TA) ****p < 0.0001) developed insulin resistance (**p < 0.01), together with reduced energy expenditure (AUC *p < 0.05), respiratory exchange ratio (AUC **p < 0.01) and grip strength (*p < 0.05). STX4 ablation in muscle also impaired mitochondrial oxygen consumption rate (****p < 0.0001). Mitochondrial morphological damage was heterogenous in STX4-depleted muscle, presenting with small fragmented mitochondria (****p < 0.0001) and decreased electron transport chain (ETC) abundance (CI ***p < 0.001, CII *p < 0.05, CIV **p < 0.01) in oxidative soleus muscle, whereas glycolytic-rich TA fibres displayed enlarged swollen mitochondria (****p < 0.0001) with no change in ETC abundance. Notably, > 60% reduction of STX4 in siSTX4 L6.GLUT4myc myotubes (****p < 0.0001) also decreased ETC abundance (CI **p < 0.01, CII ***p < 0.001, CIV **p < 0.01) without changes in mitochondrial glucose metabolism, as shown by [U-13C]glucose isotope tracing. For MQC, both skmSTX4-iKO male mice (*p < 0.05) and siSTX4 L6.GLUT4myc myotubes (*p < 0.05) showed decreased mitochondrial DNA levels alongside reduced mRNA expression of mitochondrial biogenesis genes Ppargc1a (PGC1-α, *p < 0.05) and Tfam (*p < 0.05) in skmSTX4-iKO soleus muscle and PGC1-α (mRNA **p < 0.01, protein *p < 0.05), NRF1 (mRNA **p < 0.01 and protein *p < 0.05) and Tfam (mRNA *p < 0.05) in siSTX4 L6.GLUT4myc myotubes. Furthermore, live cell imaging using the mt-Keima mitophagy biosensor in siSTX4 L6.GLUT4myc cells revealed significantly impaired mitochondrial turnover by mitophagy (*p < 0.05) and mitochondria-lysosome colocalization (*p < 0.05). STX4 depletion also reduced canonical mitophagy markers, PINK1 and PARKIN in both skmSTX4-iKO muscle (PARKIN *p < 0.05, PINK1 **p < 0.01) and siSTX4 L6.GLUT4myc myotubes (PARKIN **p < 0.01, PINK1 *p < 0.05).
    CONCLUSIONS: Our study demonstrated STX4 as a key mitochondrial regulator required for mitochondrial homeostasis in skeletal muscle.
    Keywords:  STX4; mitochondria; muscle; quality control
    DOI:  https://doi.org/10.1002/jcsm.70113
  4. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70117
    Primary-Stage Colon Cancer Impairs Muscle Energy Metabolism by Suppressing Mitochondrial Complex I Activity.
    COMUNEX group
       BACKGROUND: Colon cancer (CC), the third most common cancer worldwide, is accompanied by cachexia in 30% of patients. Its associated muscle loss directly impairs therapeutic response and survival. Early intervention is crucial, yet the underlying mechanisms of early-stage muscle dysfunction remain unclear. This study investigates mitochondrial function in skeletal muscle across different CC stages to identify early metabolic alterations.
    METHODS: The present study investigated mitochondrial function in rectus abdominus muscle biopsies from 30 patients with primary CC (83% male, mean age 67 ± 8 years), 10 patients with colorectal cancer with liver metastases (50% male, mean age 69 ± 6 years), and 17 age-matched controls (65% male, mean age 66 ± 7 years). Mitochondrial oxygen consumption was assessed using high-resolution respirometry, and transcriptional profiles were analysed via RNA sequencing.
    RESULTS: Patients with primary CC exhibited reduced complex I activity compared to controls (9.02 vs. 12.47 pmol/s/mg, p < 0.001), accompanied by transcriptional upregulation of oxidative phosphorylation (OXPHOS)-related genes. In contrast, patients with liver metastases showed more severe mitochondrial dysfunction, with reductions in both complex I (7.38 vs. 9.65 pmol/s/mg, p < 0.01) and complex II (8.36 vs. 19.73 pmol/s/mg, p < 0.05), but without the compensatory transcriptional upregulation seen in primary CC. These mitochondrial impairments occurred before detectable declines in physical function or systemic inflammation (C-reactive protein, albumin).
    CONCLUSIONS: Our findings reveal stage-specific mitochondrial dysfunction in CC, with early complex I impairment and a transient transcriptional adaptation in primary CC. These alterations precede clinical cachexia, suggesting mitochondrial dysfunction as a potential early biomarker for cancer-induced muscle loss and a target for early intervention.
    Keywords:  colon cancer; mitochondria oxidative respiration; mitochondrial function; skeletal muscle function
    DOI:  https://doi.org/10.1002/jcsm.70117
  5. Biogerontology. 2025 Nov 11. 26(6): 202
    miRNA changes with ageing and caloric restriction in male rat skeletal muscle: potential roles in muscle cell function.
    Gulam Altab, Brian J Merry, Charles W Beckett, Priyanka Raina, Ana Soriano-Arroquia, Bruce Zhang, Aphrodite Vasilaki, Katarzyna Goljanek-Whysall, João Pedro de Magalhães.
      The mechanisms underlying skeletal muscle ageing, whilst poorly understood, are thought to involve dysregulated micro (mi)RNA expression. Using young and aged rat skeletal muscle tissue, we applied high-throughput RNA sequencing to comprehensively study alterations in miRNA expression occurring with age, as well as the impact of caloric restriction (CR) on these changes. Furthermore, the function of the proteins targeted by these age- and CR-associated miRNAs was ascertained. Numerous known and novel age-associated miRNAs were identified of which CR normalised > 35% to youthful levels. Our results suggest miRNAs upregulated with age to downregulate proteins involved in muscle tissue development and metabolism, as well as longevity pathways, such as AMPK and autophagy. Furthermore, our results suggest miRNAs downregulated with age to upregulate pro-inflammatory proteins, particularly those involved in innate immunity as well as the complement and coagulation cascades. Interestingly, CR was particularly effective at normalising miRNAs upregulated with age, rescuing their associated protein-coding genes but was less effective at rescuing anti-inflammatory miRNAs downregulated with age. Lastly, the effects of a specific miRNA, miR-96-5p, identified by our analysis to be upregulated with age, were studied in cultured C2C12 myoblasts. We demonstrated miR-96-5p to decrease cell viability and markers of mitochondrial biogenesis, myogenic differentiation and autophagy. Overall, our results provide novel information regarding how miRNA expression changes in skeletal muscle, as well as the potential functional consequences of these changes and how they are ameliorated by CR.
    Keywords:  Ageing; Caloric restriction; Non-coding RNA; Sarcopenia; Transcriptomics; miRNA
    DOI:  https://doi.org/10.1007/s10522-025-10336-6
  6. Transl Oncol. 2025 Nov 10. pii: S1936-5233(25)00327-4. [Epub ahead of print]63 102596
    Nutritional strategies against skeletal muscle wasting in cancer-associated cachexia: the role of β-hydroxybutyrate and polyunsaturated fatty acids.
    Benjamin Hay, Aurélien Brun, Anne Fougerat, Vera Mazurak, Olivier Le Bacquer, Jérémie Talvas, Frédéric Capel.
      Cachexia is a multifactorial syndrome that occurs in many cancers, particularly in their advanced stages, decreasing the quality of life and lifespan of patients. One of the hallmarks of cancer-associated cachexia is skeletal muscle wasting. Multiple causes include inflammation, metabolic deregulation, energy utilization, endoplasmic reticulum and oxidative stress. Loss of skeletal muscle is characterised by an imbalance in protein homeostasis, with decreased anabolism (regulated by the Akt/GSK3/eIF2α and Akt/mTORC1 pathways) and increased catabolism (regulated by autophagy and the ubiquitin-proteasome system), as well as an impairment in myogenesis. Accumulating evidence suggests that dietary intervention of β-hydroxybutyrate, the major ketone body produced by ketogenesis, and n-3 polyunsaturated fatty acids may mitigate skeletal muscle wasting. Polyunsaturated fatty acids and β-hydroxybutyrate are able to favourably modulate inflammation, insulin resistance, unfolded protein response and stresses (such as metabolic stress and oxidative stress). A well-adapted nutritional strategy may include a "classic" diet supplemented with β-hydroxybutyrate and polyunsaturated fatty acids to maintain skeletal muscle integrity and reduce wasting.
    Keywords:  Cellular stresses; DHA; EPA; Inflammation; Ketogenic diet; Ketones; Myogenesis; Nutrition; Protein homeostasis
    DOI:  https://doi.org/10.1016/j.tranon.2025.102596
  7. Expert Opin Investig Drugs. 2025 Nov 12. 1-13
    Advancements of investigational agents for cancer cachexia: what clinical progress have we seen in the last 5 years?
    Maurizio Muscaritoli, Alessio Molfino, Simona Orlando, Federica Tambaro.
       INTRODUCTION: Cancer cachexia is a multifactorial syndrome affecting up to 80% of advanced cancer patients, associated with poor quality of life, increased cancer-treatment toxicity, and reduced survival. Despite its clinical burden, no FDA- or EMA-approved pharmacologic therapies currently exist.
    AREAS COVERED: This review covers key investigational therapies developed over the past five years, with a focus on agents targeting Growth Differentiation Factor 15 (GDF-15), including ponsegromab, AV-380, and NGM120. Additional agents include ghrelin receptor agonists (e.g. anamorelin), anabolic/catabolic modulators (ACM-001), and cannabinoids (ART27.13). The evolving role of low-dose olanzapine is also discussed in the 2023 ASCO guideline update. Advancements in early detection, including AI-driven biomarker models and the use of circulating miRNAs, are discussed.
    EXPERT OPINION: Targeting GDF-15 represents a paradigm shift in cancer cachexia treatment, with ponsegromab leading the pipeline and entering Phase 3 trials. Anamorelin has demonstrated clinical utility in improving appetite and body weight. Despite recent progress, cancer cachexia undoubtedly represents a still clinically unmet need in everyday routine praxis. The lack of standardized endpoints, heterogeneity of the syndrome, and absence of FDA-approved treatments remain major barriers to treatment implementation. Multimodal strategies combining pharmacological treatment with nutritional and rehabilitative support are likely to define future therapeutic success.
    Keywords:  Cancer cachexia; GDF-15 inhibition; anamorelin; ghrelin receptor agonist; multimodal therapy; ponsegromab
    DOI:  https://doi.org/10.1080/13543784.2025.2588640
  8. Sci Rep. 2025 Nov 11. 15(1): 39533
    Inhibition of NLRP3 inflammasome activation alleviated liver injury and wasting effect in tumor-bearing mice.
    Shuaihui Wu, Qian Cheng, Yang Shi, Mingjun Liu, Kai Tan, Bo Liao.
      This study is designed to evaluate the changes in tumor-bearing mice, as well as to assess the role of NLRP3 in muscle atrophy and its function in the liver of tumor-bearing mice. In this study, RNA-seq data from the liver of Colon26 (C26) tumor-bearing mice were used to perform pathway enrichment analysis. We established a cancer cachexia model by subcutaneous injection of C26 cells, MCC950 was injected intraperitoneally at a concentration of 30 mg/kg on day 12. On day 21, the mice were dissected, the tissues were weighed, and the specimens were fixed for subsequent staining. In our study, by analyzing RNA-seq data, we found that the inflammatory response was significantly activated in the liver of Colon26 (C26) tumor-bearing mice with up-regulation of several inflammatory cytokines, including IL-1β. Therefore, we examined the expression of NLRP3 inflammasome-related genes and found that the expression of most genes was upregulated, and the expression of NLRP3, caspase-1 and IL-1β were also upregulated. This proves that NLRP3 inflammasome is activated in the liver. In our study, on the one hand, we found that inhibition of NLRP3 inflammasome activation could alleviate liver injury and fibrosis in tumor-bearing mice. on the other hand, inhibition of NLRP3 inflammasome activation alleviates muscle atrophy and fat loss. In addition, MCC950 did not affect tumor growth and had no significant effect on the induced consumption of tumor-secreted factors. This study is the first to show that the NLRP3 inflammasome is activated in the liver of tumor-bearing mice. Pharmacological inhibition of NLRP3 inflammasome activation effectively reduces liver injury and fibrosis. Moreover, muscle atrophy and fat loss had also been alleviated.
    Keywords:  Cancer cachexia; Liver injury; MCC950; NLRP3
    DOI:  https://doi.org/10.1038/s41598-025-23323-1
  9. J Cachexia Sarcopenia Muscle. 2025 Dec;16(6): e70109
    Role of Peptides in Skeletal Muscle Wasting: A Scoping Review.
    Petar Naumovski, Bart De Spiegeleer, Aster Wakjira, Christophe Van De Wiele, Vincent Mouly, Katarzyna Goljanek-Whysall, Kauê Santana da Costa, Ewerton Cristhian Lima de Oliveira, Evelien Wynendaele, Anton De Spiegeleer.
       BACKGROUND: Systemic muscle wasting is a prevalent condition that predicts adverse health outcomes in aging and disease. Despite its clinical relevance, the development of predictive biomarkers and effective pharmacological therapies remains limited. Peptides have recently gained attention for their diverse bioactive functions, positioning them as promising biomarkers and therapeutic agents for muscle wasting.
    METHODS: This scoping review systematically identifies studies examining the direct association between well-defined peptides and clinical components of muscle wasting: muscle mass, strength and physical performance. The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Scoping Reviews (PRISMA-ScR) guidelines. A comprehensive search of Embase, PubMed and Web of Science was conducted up to 31 October 2024, focusing on original human or animal studies. Studies involving congenital or inherited muscle disorders, inflammatory myopathies and neurodegenerative diseases, such as Parkinson's disease, were excluded. A snowball approach was used to synthesize the presumed cellular pathways of identified peptides.
    RESULTS: A total of 126 studies were included: 71 (56.3%) focused on a single muscle wasting component (48 on mass, 16 on strength and 7 on performance), 31 (24.6%) examined two, 16 (12.7%) analysed all three separately, and 8 (6.3%) assessed sarcopenia as a categorical variable. Eighty-seven distinct peptides linked to muscle wasting were identified, ranging from collagen tripeptide (3 amino acids) to insulin (51 amino acids). The most studied peptides are ghrelin (14.3%), brain natriuretic peptide (BNP, 11.1%), C-peptide (11.1%), insulin (10.3%) and Szeto-Schiller 31 (SS-31, 6.3%). Most (62.1%) influence one or more of four key muscle homeostasis pathways (PI3K/Akt/mTOR, ActR/SMAD, IKK/NF-κB and AMPK/PGC1α), which regulate atrophy (via FOXO, NF-κB, SMAD2/3, glucocorticoid receptor and GSK-3β) and hypertrophy (via androgen receptors, PGC-1α and S6K). Flaws in study design and reporting were prevalent, hindering clinical translation. Sex bias was evident, with females comprising 23.9% of participants in human interventional studies and only 9.1% and 12.4% of mice and rats in rodent studies, respectively. Clinical, pre-analytical and analytical reporting gaps were common: 56.6% documented diurnal timing, food intake and activity around peptide collection; none specified storage-to-analysis duration; and only 11.5% reported detection limits for peptide measurements.
    CONCLUSION: This scoping review highlights the potential of peptides as biomarkers and intervention targets for muscle wasting. It connects the cellular receptors and signaling pathways linking peptides with skeletal muscle wasting. Improving clinical translation requires addressing study design limitations, incorporating more representative study populations and adhering to standardized reporting guidelines. The application of machine learning can support the identification of novel bioactive peptides.
    Keywords:  cachexia ; muscle wasting; peptides; sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.70109
  10. Nat Metab. 2025 Nov 12.
    Reawakening cAMP signalling in cancer cachexia.
    Honglei Ji, Maria Rohm.
      
    DOI:  https://doi.org/10.1038/s42255-025-01417-4
  11. Neuromuscul Disord. 2025 Oct 25. pii: S0960-8966(25)00985-X. [Epub ahead of print]56-57 106258
    Novel missense variants associated with GNE myopathy.
    Johanna Ranta-Aho, Viviana Cetrangolo, Luca Bello, Giuliana Capece, Elena Pegoraro, Maria Francesca Di Feo, Violeta Mihaylova, Hans H Jung, Fabien Hauw, Tanya Stojkovic, Anthony Behin, Norma Romero, Thierry Maisonobe, Matteo Lucchini, Miguel Oliveira Santos, Massimiliano Mirabella, Giorgio Tasca, Marco Savarese, Bjarne Udd, Mridul Johari.
      GNE myopathy is a rare autosomal recessive skeletal muscle disorder characterized by progressive distal muscle weakness, typically starting in the lower legs and gradually involving proximal muscle groups. It is an autosomal recessive disease, caused by biallelic variants in GNE. To date, over 350 causative GNE variants have been reported, however, establishing genotype-phenotype correlation remains difficult due to clinical heterogeneity and limited patient numbers. In this study, we describe 20 unrelated European families with a diagnosis of GNE myopathy and biallelic GNE variants identified in either homozygosity or compound heterozygosity. While the majority of variants observed in our cohort have been previously reported, we identified five novel missense variants: p.(G355R), p.(A679T), p.(I709T), p.(V727G), and p.(V744I). Using in silico prediction tools and ACMG/AMP criteria, we classified p.(G355R) and p.(V727G) as likely pathogenic. The clinical features of our cohort were consistent with the classical presentation of GNE myopathy. Our findings contribute new genotype data and support ongoing efforts to refine variant interpretation in GNE myopathy. This study expands the mutational spectrum of GNE and reinforces the phenotypic consistency across diverse populations.
    Keywords:  GNE myopathy; foot drop; neuromuscular disease; rare disease; rimmed vacuoles; sialic acid
    DOI:  https://doi.org/10.1016/j.nmd.2025.106258
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