bims-musmir 2026-03-08 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–03–08
24 papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Molecular Insights into the Regulatory Mechanisms Mediated by Hypoxia-Conditioned Skeletal Muscle Exosomal miRNAs.
Lactate supplementation modulates molecular and functional responses during chronic neuromuscular electrical stimulation in male rats.
Silymarin alleviates cisplatin-induced cachexia via modulating tripartite motif containing 63 (TRIM63) and myogenin.
HIF2 drives PTHrP-mediated cancer cachexia.
β-Nicotinamide mononucleotide preserves muscle strength in septic male mice.
A closed tumor-immune-brain circuit in cancer cachexia.
Preclinical assessment of GNEwt/bi-shRNA-GNEM743T lipoplex product development for GNE myopathy.
Age-related adiponectin resistance in human skeletal muscle dysfunction: in vivo and in vitro evidence.
Piezo1-dependent activation of stromal cells ignites muscle inflammation in exercise and injury and is associated with inflammaging.
Tumor-induced orexigenic imbalance lowers protein appetite and drives early organ wasting symptoms.
Astrocyte-specific FoxF2 modulates immune and myelin repair: Evidence from multiple sclerosis lesions and an animal model.
Cell free miRNAs are pharmacodynamic biomarkers for enhanced Dicer activity by Enoxacin in human patients with Amyotrophic lateral sclerosis.
Mitochondrial complex-derived ROS induces lysosomal dysfunction and impairs autophagic flux in human cells carrying the APOE4 allele.
Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.
SLC4A1 mutations that cause distal renal tubular acidosis alter cytoplasmic pH and cellular autophagy.
Malnutrition, cachexia and sarcopenia as susceptibility factors for cardiovascular complications in patients with cancer.
Miglustat: a first-in-class enzyme stabilizer for cipaglucosidase alfa for the treatment of late-onset Pompe disease.
RNA localization to nuclear speckles follows splicing logic.
Beyond cellular distress: reframing GDF15 as a lipid-sensitive metabolic signal.
Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.
Chronic activation of p38α in skeletal muscle causes necrotic changes, but also abolishes expression of MK2, MK3 and MKK6 and the muscle recovers.
Constitutive neuronal expression and disease-associated upregulation of chitinases in amyotrophic lateral sclerosis.
The S100A8/A9 complex promotes food intake and prevents adipose tissue loss during cancer cachexia in mice.
Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.

Biomark Insights. 2026 ;21 11772719261427170

Molecular Insights into the Regulatory Mechanisms Mediated by Hypoxia-Conditioned Skeletal Muscle Exosomal miRNAs.

Haijiao Wang, Baochang Shi, Wenting Song, Lu Lu, Akhilesh K Bajpai, Qiu Li.

   Background: Hypoxia alters skeletal muscle metabolism and function through complex regulatory mechanisms, including exosome-mediated microRNA (miRNA) signaling.
Objectives: This study profiled exosomal miRNAs from hypoxic human skeletal muscle cells (HSMCs) to explore their roles in hypoxic adaptation.
Design: Human skeletal muscle cells were cultured under normoxic or hypoxic conditions, and secreted exosomes were isolated for comprehensive molecular profiling. High-throughput miRNA sequencing combined with integrative bioinformatic analyses was used to uncover hypoxia-responsive regulatory networks and key miRNA hubs involved in skeletal muscle adaptation.
Methods: HSMCs were cultured under normoxic or hypoxic conditions for 24 hours. Exosomes were isolated and characterized by transmission electron microscopy, nanoparticle tracking analysis, and immunoblotting. Exosomal miRNAs (n = 3 per group) were profiled using high-throughput sequencing, followed by differential expression, target prediction, enrichment, and network analyses.
Results: Isolated exosomes displayed typical morphology (mean size: 82.4 ± 3.2 nm) and expressed markers CD9, CD63, and TSG101. Seventy-four miRNAs were significantly dysregulated under hypoxia (23 upregulated, 51 downregulated; FDR < 0.05, |log2FC| ⩾ 1), including upregulated hsa-miR-210-3p and downregulated hsa-miR-486-5p, hsa-miR-127-3p, and hsa-miR-126-3p. Predicted targets (~2000 genes) included 451 genes differentially expressed in hypoxic versus normoxic skeletal muscle cells. Functional enrichment highlighted cancer-related, MAPK, PI3K-Akt, and HIF-1 signaling pathways, along with muscle differentiation processes. Network analysis identified hsa-miR-20a-5p as a central regulatory hub (46 targets), followed by hsa-miR-24-3p and hsa-miR-152-3p. hsa-miR-24-3p showed the strongest disease associations in the miRNA-disease network.
Conclusions: Hypoxia induces distinct exosomal miRNA signatures in skeletal muscle, regulating genes involved in differentiation, migration, and stress response. These findings suggest that exosome-mediated miRNA signaling contributes to hypoxia-driven muscle adaptation and intercellular communication.

Keywords:  exosome; hypoxia; miRNA sequencing; normoxia; skeletal muscle

DOI:  https://doi.org/10.1177/11772719261427170
Physiol Rep. 2026 Mar;14(5): e70790

Lactate supplementation modulates molecular and functional responses during chronic neuromuscular electrical stimulation in male rats.

Toshinori Yoshihara, Yasushi Koriyama, Sakura Ogawa, Hisashi Naito.

  Lactate is increasingly recognized as a signaling molecule that modulates muscle plasticity. We examined the effects of oral L-sodium lactate supplementation on skeletal muscle adaptation to chronic neuromuscular electrical stimulation (NMES) in rats. Male Wistar rats received oral lactate or water before either a single NMES session (acute) or repeated sessions over 2 weeks (chronic). We assessed muscle weight, strength, myonuclear-associated protein expression (PCM1), protein synthesis (puromycin incorporation), signaling responses (mechanistic target of rapamycin pathway), and mitochondrial-related protein expression (PGC-1α, OXPHOS, and citrate synthase). The oxidative soleus and glycolytic plantaris muscles were analyzed. Lactate supplementation was associated with greater increases in muscle mass and torque during chronic NMES, particularly in the soleus. PCM1 abundance and myofibrillar puromycin incorporation were higher in the lactate-supplemented group, although there were no significant changes in c-Myc or rpS6. PGC-1α expression was elevated in the plantaris muscle, indicating muscle-type-specific mitochondrial modulation. However, the expression levels of the lactate transporters (MCT1 and MCT4) and GPR81 remained largely unchanged in response to oral lactate. Collectively, these findings suggest that oral lactate is associated with distinct molecular signatures and functional outcomes during chronic NMES in a muscle type-dependent manner, warranting further studies using morphological and muscle-specific functional assessments.

Keywords:  lactate supplementation; mitochondrial biogenesis; myonuclear; neuromuscular electrical stimulation; protein synthesis

DOI:  https://doi.org/10.14814/phy2.70790
Indian J Pharmacol. 2026 Mar 01. 58(2): 101-108

Silymarin alleviates cisplatin-induced cachexia via modulating tripartite motif containing 63 (TRIM63) and myogenin.

Shreya Das, Jyotika, Ritu Pahuja, Sapana Kushwaha, Richa Shrivastava.

   OBJECTIVE: Cachexia is one of the major chemotherapy-induced adverse effects, characterized by gradual depletion of muscle mass. Currently, there is no specific treatment for cachexia. This study aims to evaluate the role of silymarin in attenuating muscle wasting in a model of cisplatin-induced cachexia.
MATERIALS AND METHODS: Female Swiss albino mice were divided into three groups (n = 6) and received the treatment according to their group for 7 days: NC (Normal Control, receiving normal saline), CP (Cisplatin, receiving cisplatin 3 mg/kg i.p.) and SY+CP (Silymarin+Cisplatin, receiving silymarin 100 mg/kg orally two hours before cisplatin 3mg/kg i.p). Body weight, muscle weight, tumor necrosis factor alpha (TNF-α), and GSH levels were measured, and muscle histopathological studies were performed.
RESULTS: Silymarin prevented cisplatin-induced damage in the triceps, quadriceps, and gastrocnemius muscles. Cisplatin administration altered tissue architecture and decreased the size and cross-sectional area of all three muscle fibers, which were significantly restored in the silymarin-treated group. Muscle tissue homogenates from the silymarin-treated group exhibited higher levels of reduced glutathione compared to the cisplatin group. The elevated serum TNF-α levels in the cisplatin group were decreased from 183 ± 1.66 pg/mL to 117.40 ± 10.47 pg/mL in the silymarin-treated mice. Tripartite motif-containing 63 (TRIM63), a muscle atrophy marker, was upregulated, and myogenin, a marker of myogenesis, was decreased by cisplatin, and the expression of both markers was reversed upon silymarin treatment.
CONCLUSIONS: Silymarin attenuates cisplatin-induced cachexia through TRIM63 suppression, myogenin restoration, and reduced oxidative and inflammatory stress.

Keywords:  Chemotherapy; muscle wasting; myogenesis; oxidative stress; skeletal muscle

DOI:  https://doi.org/10.4103/ijp.ijp_136_25
Trends Mol Med. 2026 Mar 03. pii: S1471-4914(26)00008-0. [Epub ahead of print]

HIF2 drives PTHrP-mediated cancer cachexia.

Jiaxin Yan, Wenhui Wang, Gaofei Wei.

  Cachexia and hypercalcemia frequently complicate advanced renal cancer. A recent Nature Medicine study by Abu-Remaileh et al. shows that pharmacologic hypoxia-inducible factor 2 (HIF2) inhibition rapidly suppresses parathyroid hormone-related protein (PTHrP), reverses metabolic wasting, and normalizes calcium levels, redefining these paraneoplastic syndromes as targetable endocrine disorders rather than secondary consequences of tumor burden.

Keywords:  HIF2; PTHrP; cancer cachexia; renal cell carcinoma

DOI:  https://doi.org/10.1016/j.molmed.2026.01.004
Sci Rep. 2026 Mar 17.

β-Nicotinamide mononucleotide preserves muscle strength in septic male mice.

Mari Saida, Noritaka Saeki, Hiroshi Sakai, Jun Iwanami, Atsushi Yokoyama, Shun Sawatsubashi, Motoi Kanagawa, Norio Sato, Yuuki Imai.

  Sepsis remains a leading cause of mortality and long-term disability, with survivors frequently developing intensive care unit-acquired weakness (ICU-AW) as part of post-intensive care syndrome. To identify a nutritional therapy for ICU-AW, we investigated the mechanisms underlying sepsis-induced skeletal muscle dysfunction using a cecal slurry-induced sepsis mouse model. Although body weight and skeletal muscle mass recovered 14 days after sepsis induction, muscle strength remained impaired, accompanied by persistent mitochondrial abnormalities. Transcriptomic analysis revealed that the pathways termed the 'sirtuin signaling pathway' and 'mitochondrial dysfunction' significantly enriched and Sirt3, a major mitochondrial nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, was downregulated. Biochemical analyses confirmed increased acetylated lysine of mitochondrial proteins in septic muscle tissue. Among these proteins, mass spectrometry detected several proteins in the acetylated band, including multiple complex I subunits. Whether these are direct SIRT3 targets remains to be determined. Knockdown of Sirt3 in C2C12 myotubes impaired mitochondrial respiration, whereas treatment with β-nicotinamide mononucleotide (β-NMN) partially rescued energy production. In vivo, acute-phase administration of β-NMN preserved mitochondrial morphology and skeletal muscle strength without altering muscle mass. These findings demonstrate that sepsis induces mitochondrial dysfunction and persistent muscle weakness associated with Sirt3 downregulation, and highlights β-NMN supplementation as a promising NAD⁺-targeted therapeutic strategy for mitigating ICU-AW.

Keywords:   β-NMN; Mitochondrial respiration; Sepsis; Sirt3; Skeletal muscle weakness

DOI:  https://doi.org/10.1038/s41598-026-43172-w
Cancer Cell. 2026 Mar 05. pii: S1535-6108(26)00105-4. [Epub ahead of print]

A closed tumor-immune-brain circuit in cancer cachexia.

Felix Clemens Richter, Joel Xu En Wong, Andreas Bergthaler.

Cancer-associated cachexia is a complex metabolic syndrome leading to sustained body weight loss and tissue wasting. In this issue of Cancer Cell, Shi et al. identify a novel GDF15-driven tumor-immune-brain crosstalk, resulting in altered systemic metabolism and tissue catabolism.

DOI: https://doi.org/10.1016/j.ccell.2026.02.007
Future Sci OA. 2026 Dec;12(1): 2635722

Preclinical assessment of GNEwt/bi-shRNA-GNEM743T lipoplex product development for GNE myopathy.

Fabienne Kerneis, Christopher M Jay, Donald Rao, Jeremy Winchester, Alexander Nemunaitis, Emily Nemunaitis, Ernest Bognar, Gladice Wallraven, Laura Stanbery, Adam Walter, Sep Sarshar, John Nemunaitis.

   AIMS: GNE myopathy is a heredity disease of unmet medical need associated with progressive skeletal muscle wasting, atrophy and weakness caused by mutations in the GNE gene. GNE plays a pivotal role in sialic acid production. Sialic acid is a critical part of glycoprotein, ganglioside and glycolipid cell-cell interaction which is necessary for normal skeletal muscle function. Previously we demonstrated safety and efficacy of the GNEwt gene lipoplex in one patient.
METHODS: We engineered GNEM743T and dual function GNEwt/bi-shRNA plasmids to evaluate GNEM743T specific knockdown and GNEwt expression. Knockdown efficiency, protein expression, and functional rescue were assessed. A dose range study in mice quantified plasmid delivery and human GNE expression in muscle.
RESULTS: We demonstrate effective plasmid function via knockdown of the GNEM743T gene mutation and concurrent expression of GNEwt gene in a dose dependent manner. Similar in vitro increase in sialic acid production is shown between prior single function plasmid and GNEwt/bi-shRNA-GNEM743T dual function plasmid. Moreover, we demonstrate murine in vivo muscle delivery and expression of GNEwt mRNA from the GNEwt/bi-shRNA-GNEM743T plasmid delivered via DOTAP-Cholesterol lipoplex following intravenous injection.
CONCLUSION: These results encourage future studies, potentially leading toward clinical testing of GNEwt/bi-shRNA-GNEM743T lipoplex for GNE myopathy.

Keywords:  GNE; GNE M743T; Plasmid; bi-shRNA; myopathy

DOI:  https://doi.org/10.1080/20565623.2026.2635722
J Transl Med. 2026 Mar 05.

Age-related adiponectin resistance in human skeletal muscle dysfunction: in vivo and in vitro evidence.

Surina Surina, Lucia Scisciola, Manuela Giovanna Basilicata, Ada Pesapane, Rosaria Anna Fontanella, Nunzia Balzano, Alberta Maria Maddalena Palazzo, Asad Zia, Giovanni Tortorella, Zeeshan Ulfat, Maryam Arshad, Rashmi Joshi, Maria Teresa Vietri, Annalisa Capuano, Giuseppe Paolisso, Michelangela Barbieri.

   BACKGROUND: Sarcopenia is an age-related condition characterized by the progressive decline of skeletal muscle mass and function. Although adiponectin is known for its anti-inflammatory and insulin-sensitizing effects that support muscle regeneration, paradoxically, elevated levels in older adults are linked to decreased muscle mass, strength, and performance. This study aimed to investigate the relationship between adiponectin levels, age, body composition, and functional status in elderly individuals, as well as to perform in vitro analyses of adiponectin resistance.
METHODS: A cohort of 393 elderly subjects underwent anthropometric, bioimpedance, and functional assessments. Plasma adiponectin levels were measured by ELISA, and AdipoR1/AdipoR2 expression in peripheral blood mononuclear cells (PBMCs) was evaluated. In vitro, human skeletal muscle cells (SkMCs) were exposed to high concentrations (50 µM) of AdipoRon, a dual AdipoR1/AdipoR2 agonist, for 24 and 72 h. Analyses include cell viability, oxidative stress, protein homeostasis, autophagy, proteasome activity, and lipid metabolism.
RESULTS: In elderly subjects, plasma adiponectin levels negatively correlated with BMI (r = -0.129; p = 0.03), lean mass (r = -0.252; p = 0.001), muscle mass (r = -0.296; p = 0.001), and physical performance (SPPB score; r = -0.163; p = 0.007). After adjusting for BMI and fat mass, adiponectin levels positively correlated with age (r = 0.281; p = 0.001). AdipoR2 expression in peripheral blood mononuclear cells was inversely associated with both age and adiponectin levels, suggesting adiponectin resistance in aging. In vitro, high dose of AdipoR agonist -AdipoRon exposure leads to oxidative stress, impaired proteostasis, dysregulated lipid metabolism, AdipoR2 receptor downregulation, and reduced cell viability. Together, these findings support a model in which elevated adiponectin in aging reflects adiponectin resistance and cellular stress rather than beneficial adiponectin signaling, contributing to muscle dysfunction.
CONCLUSIONS: These findings highlight a shift in adiponectin signaling during aging, with the downregulation of AdipoR2 promoting systemic adiponectin resistance. Excessive AMPK activity, in the context of impaired AdipoR2 function, contributes to redox imbalance and metabolic dysfunction in the skeletal muscle, favoring a "senescent-like" phenotype.

Keywords:  AdipoRon; Adiponectin resistance; Aging; Cellular senescence; Sarcopenia; Skeletal muscle dysfunction

DOI:  https://doi.org/10.1186/s12967-026-07959-9
Nat Immunol. 2026 Mar;27(3): 543-555

Piezo1-dependent activation of stromal cells ignites muscle inflammation in exercise and injury and is associated with inflammaging.

P Kent Langston, Jayashree Vijaya Raghavan, Christophe Benoist, Diane Mathis.

As the actuator of movement and a key regulator of organismal metabolism, skeletal muscle is a site at which inflammatory responses must be carefully calibrated to counteract stressors while preventing protracted functional impairments. Exercise, injury and aging are common forms of stress associated with inflammation; yet the specific inducers and sensors driving such inflammation remain poorly characterized. Multipronged assessment of acute and chronic endurance exercise models uncovered a role for muscle mesenchymal stromal cells in transducing exercise-induced mechanical stress into local inflammatory responses and that the mechanosensitive ion channel Piezo1 is the primary molecular sensor. Mechanosensing by stromal cells is also necessary for appropriately timed inflammatory and myogenic responses to acute muscle injury and is associated with age-related muscle inflammation. These findings highlight sensing of altered tissue stiffness by Piezo1 on muscle mesenchymal stromal cells as a fundamental mechanism of stress-induced immunomodulation in skeletal muscle.

DOI: https://doi.org/10.1038/s41590-026-02435-4
Nat Commun. 2026 Mar 06.

Tumor-induced orexigenic imbalance lowers protein appetite and drives early organ wasting symptoms.

Afroditi Petsakou, Elizabeth Filine, Matthew Li, Yuchen Chen, Alice Zheng, Norbert Perrimon.

Cancer cachexia (CC) is characterized by organ wasting and ensuing involuntary weight loss. Despite advances, underlying mechanisms initiating CC remain unclear, including early symptoms like anorexia. Here, we use a fly gut-tumor model with a precise time-window before organ wasting starts. We show that tumor-induced factors involved in inflammation (unpaired 3/ Interleukin-6-like) and reduced insulin signaling (ImpL2/ Insulin Growth Factor Binding Protein) decrease NPF (Neuropeptide F/ Neuropeptide Y) in the brain prior to organ wasting. This early NPF decrease triggers low protein-specific food appetite and anorexia. We find that ImpL2 reduces NPF signaling while upd3 helps by concurrently affecting the blood brain barrier. Tumor-induced NPF decrease, and early reduction of protein appetite drive the onset of weight loss and exacerbate the risk of death during organ wasting. Altogether, we provide evidence for an early orexigenic brain imbalance causing low protein appetite that regulates the onset and outcome of organ wasting.

DOI: https://doi.org/10.1038/s41467-026-70074-2
J Neuroimmunol. 2026 Feb 26. pii: S0165-5728(26)00044-5. [Epub ahead of print]415 578896

Astrocyte-specific FoxF2 modulates immune and myelin repair: Evidence from multiple sclerosis lesions and an animal model.

Karina Damsbo, Azadeh Reyahi, Ali M Nik, Mhaned Oubounyt, Anna Weber, Kirsten H Hyrlov, Christina Kingo, Maria L Foged, Mie Waede, Jan Baumbach, Richard Reynolds, Peter Carlsson, Zsolt Illes, Maria L Elkjaer.

  As multiple sclerosis (MS) progresses, myelin repair becomes inefficient. To gain insight into the underlying causes, we RNA-sequenced postmortem brain tissues from 4 and 6 patients, comparing remyelinating versus chronically active MS lesions. We identified the transcription factor FoxF2 as highly expressed within remyelinating lesions. Immunohistochemistry and in situ hybridization showed FoxF2 co-expression in GFAP-positive astrocytes, suggesting a subpopulation of astrocytes with a potential role in repair. To investigate how FoxF2 may influence repair, we examined cuprizone (CPZ)-induced de- and remyelination in CreERT2 FoxF2flox/flox conditional knockout (FoxF2 KO) mice. In the absence of FoxF2, RNA sequencing of the isolated corpus callosum (CC) showed high gene activation during demyelination and reduced gene activation during remyelination. Upregulated genes in FoxF2 KO mice were related to immune functions and metabolism. Specifically, upregulation of MHC-II and TNF-associated pathway genes, while astrocyte-specific FoxF2 deletion significantly reduced Tgfb2 and Tgfbr2 expression, implicating disrupted TGF-β signaling. The FoxF2 KO mice exhibited upregulation of ribosomal and sphingolipid metabolism genes during demyelination, while structurally related genes, including Mog expression, were impaired in the FoxF2 KO mice. Using network analysis to group highly correlated genes in the CC transcriptome, we identified gene regulatory network (GRN) changes. GRN analysis revealed the loss of FoxF2-associated modules (e.g., Foxf2-Bach2, Nfe2l1-Mafg), indicating impaired coordination of anti-inflammatory and regenerative pathways. In conclusion, analysis of MS white matter (WM) lesions and subsequent experimental data demonstrates that FoxF2 plays a role in regulating repair and gene networks associated with immune regulation, metabolism, and structural remodeling.

Keywords:  Astrocytes; Cuprizone; FoxF2; Progressive multiple sclerosis; Remyelination; TGFβ-receptor 2; White matter brain lesions

DOI:  https://doi.org/10.1016/j.jneuroim.2026.578896
Mol Ther. 2026 Mar 05. pii: S1525-0016(26)00187-5. [Epub ahead of print]

Cell free miRNAs are pharmacodynamic biomarkers for enhanced Dicer activity by Enoxacin in human patients with Amyotrophic lateral sclerosis.

Iddo Magen, Hannah Marlene Kaneb, Maria Masnata, Nisha Pulimood, Anna Emde, Angela Genge, Eran Hornstein.

The activity of the RNase III enzyme DICER is downregulated in both sporadic and genetic forms of Amyotrophic Lateral Sclerosis (ALS). Accordingly, hundreds of microRNAs (miRNAs) are broadly downregulated, leading to de-repression of their mRNA targets. Enoxacin is a fluoroquinolone that enhances DICER activity and miRNA biogenesis. Here, we tested for the first time the molecular effect of Enoxacin on miRNA biogenesis in ALS patients and demonstrated that Enoxacin's engagement with DICER can be pharmacodynamically monitored via miRNA levels in human subjects. In an investigator-initiated, first-in-human study (REALS1), we explored miRNAs as pharmacodynamic biomarkers of DICER activation. Patients with sporadic ALS received oral Enoxacin twice daily for 30 days in a double-blind, randomized clinical trial. The study demonstrated comparable Enoxacin levels in plasma and cerebrospinal fluid (CSF). Furthermore, an increase in cell-free miRNA levels in both plasma and CSF at all time points following Enoxacin treatment (400 mg or 800 mg/day), was measured relative to baseline. Additionally, no serious adverse events were reported. In conclusion, pharmacological enhancement of DICER activity by Enoxacin increases miRNA biogenesis in patients with ALS. These results support further investigation of Enoxacin efficacy in larger clinical trials.

DOI: https://doi.org/10.1016/j.ymthe.2026.03.002
Biochim Biophys Acta Mol Basis Dis. 2026 Mar 03. pii: S0925-4439(26)00060-8. [Epub ahead of print] 168211

Mitochondrial complex-derived ROS induces lysosomal dysfunction and impairs autophagic flux in human cells carrying the APOE4 allele.

Sandra A Niño, Oskar Barrios-Camus, Eduardo Silva-Pavez, J César Cárdenas, Christian González-Billault.

  The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer's disease (sAD), yet its cell-autonomous effects remain poorly understood. While young, asymptomatic APOE4 carriers exhibit abnormal brain metabolism, the mechanistic link between mitochondrial dysfunction and lysosomal-autophagic failure remains unclear. In this study, we conducted a comprehensive analysis of primary human fibroblasts from APOE3 controls, APOE4, and sAD donors to assess mitochondrial bioenergetics, oxidative stress, autophagy, and lysosomal function. APOE4 fibroblasts displayed increased mitochondrial content-associated markers (PGC1α, mtDNA) accompanied by reduced respiratory capacity, elevated proton leak, and excessive mitochondrial ROS. In parallel, APOE4 fibroblasts showed impaired autophagic flux and reduced LC3-TOMM20 colocalization, indicating defective mitophagy. Lysosomal proteolytic activity, assessed using DQ-BSA, was significantly reduced and remained unresponsive under to starvation, in contrast to the partial recovery observed in sAD cells. Pharmacological targeting of mitochondrial ROS with site-specific inhibitors revealed that complex III-derived ROS is the predominant driver of redox stress in APOE4 fibroblasts, while complex I contributes primarily in sAD. Notably, selective inhibition of complex III-derived ROS with S3QEL restored lysosomal degradation, autophagic flux, and mitochondrial respiration in APOE4 cells. Together, these findings demonstrate that mitochondrial oxidative stress disrupts the mitochondria-lysosome axis in an APOE4-specific manner, revealing early and mechanistically distinct vulnerabilities that may precede neurodegeneration. Our results challenge the notion that APOE4 merely amplifies AD pathology and instead identity site-specific redox signaling as a promising target for allele-informed interventions.

Keywords:  APOE4; Autophagy; Human fibroblasts; Lysosome; Mitochondria; Mitochondrial complex III; S3QEL

DOI:  https://doi.org/10.1016/j.bbadis.2026.168211
Mol Biol Cell. 2026 Mar 04. mbcE25110560

Mitophagy Enhancement Delays Mouse Mesenchymal Stem Cell Senescence by Attenuating the Senescence-Associated Secretory Phenotype.

Yingying Sun, Xudong Fu, Yi Li, Mengfan Peng, Lei Yang.

Aging is a complex biological process that heightens susceptibility to age-related diseases, often driven by declining mitochondrial function. Mitophagy, the selective removal of damaged mitochondria, is a key quality-control mechanism essential for maintaining cellular health, and its decline has been closely linked to aging. However, the specific role of mitophagy in cellular senescence, a hallmark of aging, remains insufficiently understood, largely due to the lack of methods to manipulate mitophagy. In this study, we employed UMI-77, a new potent mitophagy activator, to evaluate its effects on senescence in mouse mesenchymal stem cells (MSCs). Our results show that UMI-77 preserves mitochondrial integrity and effectively delays cellular senescence through mitophagy. Mechanistically, UMI-77 markedly suppressed the senescence-associated secretory phenotype (SASP). Together, our findings reveal a new anti-aging therapeutic application for UMI-77 by targeting senescence-associated chronic inflammation through mitophagy induction and SASP reduction.

DOI: https://doi.org/10.1091/mbc.E25-11-0560
Elife. 2026 Mar 04. pii: RP108253. [Epub ahead of print]14

SLC4A1 mutations that cause distal renal tubular acidosis alter cytoplasmic pH and cellular autophagy.

Grace Essuman, Midhat Rizvi, Ensaf Almomani, Shahid A K M Ullah, Sarder M A Hasib, Forough Chelangarimiyandoab, Priyanka Mungara, Manfred J Schmitt, Marguerite Hureaux, Rosa Vargas-Poussou, Nicolas Touret, Emmanuelle Cordat.

  Distal renal tubular acidosis (dRTA) is a disorder characterized by the inability of the collecting duct system to secrete acids during metabolic acidosis. The pathophysiology of dominant or recessive SLC4A1 variant-related dRTA has been linked with the mis-trafficking defect of mutant kAE1 protein. However, in vivo studies in kAE1 R607H dRTA mice and humans have revealed a complex pathophysiology implicating a loss of kAE1-expressing intercalated cells and intracellular relocation of the H+-ATPase in the remaining type-A intercalated cells. These cells also displayed accumulation of ubiquitin and p62 autophagy markers. The highly active transport properties of collecting duct cells require the maintenance of cellular energy and homeostasis, a process dependent on intracellular pH. Therefore, we hypothesized that the expression of dRTA variants affects intracellular pH and autophagy pathways. In this study, we report the characterization of newly identified dRTA variants and provide evidence of abnormal autophagy and degradative pathways in mouse inner medullary collecting duct cells and kidneys from mice expressing kAE1 R607H dRTA mutant protein. We show that reduced transport activity of the kAE1 variants correlated with increased cytosolic pH, reduced ATP synthesis, attenuated downstream autophagic pathways pertaining to the fusion of autophagosomes and lysosomes and/or lysosomal degradative activity. Our study elucidated a close relationship between the expression of defective kAE1 proteins, reduced mitochondrial activity, and decreased autophagy and protein degradative flux.

Keywords:  cell biology; kidney; mouse; transgenic animals

DOI:  https://doi.org/10.7554/eLife.108253
Front Pharmacol. 2026 ;17 1762196

Malnutrition, cachexia and sarcopenia as susceptibility factors for cardiovascular complications in patients with cancer.

Ionas Papasotiriou, Anastasios Tentolouris, Ioannis Ntanasis-Stathopoulos, Michalis Liontos.

  Cancer remains a leading cause of morbidity and mortality, although cancer survivorship has increased impressively in the past decades. Patients with cancer often face cardiovascular complications, either due to cancer itself or due to anti-cancer therapy, that may affect their quality of life and survival. Several studies have examined possible risk factors for cardiovascular susceptibility and/or cancer treatment-related cardiotoxicity, and some of them found a link between nutritional status and cardiovascular complications. In this review, we discuss the role of malnutrition, sarcopenia and cachexia, as susceptibility factors for cardiovascular complications and cardiotoxicity in cancer. The limited evidence shows that poor nutritional status and sarcopenia or cachexia is related to a cardiovascular burden in this population, and with a higher risk for cancer treatment-related cardiotoxicity. This relation may be mediated through several mechanisms and pathways, including cardiac wasting. Nutritional interventions should be examined for their effectiveness in reducing cardiovascular complications in patients with cancer, alongside with novel drugs that can prevent both skeletal and cardiac muscle wasting.

Keywords:  cachexia; cancer; cardiotoxicity; malnutrition; sarcopenia

DOI:  https://doi.org/10.3389/fphar.2026.1762196
Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261425686

Miglustat: a first-in-class enzyme stabilizer for cipaglucosidase alfa for the treatment of late-onset Pompe disease.

Robert J Hopkin, Barry J Byrne, Mazen M Dimachkie, Priya S Kishnani, Tahseen Mozaffar, Mark Roberts, Benedikt Schoser, Nadine A M E van der Beek, Ans T van der Ploeg, Stephan Wenninger, Jon Brudvig, Brian Fox, Fred Holdbrook, Vipul Jain, Franklin Johnson, Jennifer Zhang, Giancarlo Parenti.

  Late-onset Pompe disease (LOPD) is a rare inherited disorder caused by deficiency of the lysosomal enzyme acid α-glucosidase (GAA), leading to an accumulation of lysosomal glycogen in tissues, profoundly affecting muscles. Patients with LOPD typically have some residual GAA activity but experience progressive skeletal muscle dysfunction resulting in muscle weakness and respiratory failure. Enzyme replacement therapy (ERT) with alglucosidase alfa, a recombinant human GAA (rhGAA), was the first disease-specific therapy for Pompe disease. Despite efficacy in the first years of use, many patients receiving alglucosidase alfa experience a decline in function over time. This may reflect the inherent challenges associated with rhGAA ERT, such as enzyme inactivation at the near-neutral pH of blood, inefficient target cell uptake, and a necessity for complete lysosomal processing once inside target cells. Cipaglucosidase alfa, a second-generation rhGAA, aims to address these challenges through natural enrichment with bis-mannose-6-phosphate-containing N-glycans to enhance cellular uptake while retaining capacity for complete postdelivery processing. Co-administration of cipaglucosidase alfa with the small molecule stabilizer miglustat (N-butyldeoxynojirimycin) enhances cipaglucosidase alfa stability in the bloodstream after infusion. We discuss published and new preclinical and clinical data on the efficacy and safety of miglustat in combination with cipaglucosidase alfa for treating LOPD. Studies in Pompe mouse models and patients with Pompe disease showed that stabilization by miglustat improved cipaglucosidase alfa exposure and availability for uptake into target tissues and was associated with improved functional outcomes and biomarker levels compared with cipaglucosidase alfa alone. In patients with Pompe disease, the once every 2 weeks dosing regimen of miglustat was well tolerated, with a low frequency of miglustat-related gastrointestinal events compared with daily miglustat regimens at higher doses used in the treatment of other diseases. Trial registration: New data are reported for NCT02675465 (ATB200-02), NCT03729362 (PROPEL), and NCT04138277 (PROPEL open-label extension, ATB200-07); all registered at ClinicalTrials.gov (https://clinicaltrials.gov).

Keywords:  LOPD; Pompe disease; cipaglucosidase alfa; miglustat

DOI:  https://doi.org/10.1177/26330040261425686
Nucleic Acids Res. 2026 Feb 24. pii: gkag174. [Epub ahead of print]54(5):

RNA localization to nuclear speckles follows splicing logic.

Li Wen, Mauricio A Arias, Xinqi Fan, Joyce Xie, Sneha Paul, Susan E Liao, Marek Sobczyk, Oded Regev, Jingyi Fei.

Nuclear speckles are membraneless organelles implicated in multiple RNA processing steps. In this work, we systematically characterize the sequence logic determining RNA localization to nuclear speckles. We find extensive similarities between the speckle localization code and the RNA splicing code, even for transcripts that do not undergo splicing. Specifically, speckle localization is enhanced by the presence of unspliced exon-like or intron-like sequence features. We demonstrate that interactions required for early spliceosomal complex assembly contribute to speckle localization. We also show that speckle localization of isolated endogenous exons is reduced by disease-associated single nucleotide variants. Finally, we find that speckle localization strongly correlates with splicing kinetics of splicing-competent constructs and is linked to the decision between exon inclusion and skipping. Together, these results suggest a model in which RNA speckle localization is associated with the formation of the early spliceosomal complex and enhances the efficiency of splicing reactions.

DOI: https://doi.org/10.1093/nar/gkag174
Curr Opin Lipidol. 2026 Apr 01. 37(2): 45-51

Beyond cellular distress: reframing GDF15 as a lipid-sensitive metabolic signal.

Dongdong Wang, Logan K Townsend, Gregory R Steinberg.

   PURPOSE OF REVIEW: Growth differentiation factor-15 (GDF15) is widely described as a hormone that conveys somatic distress to the brain, yet this framework does not explain why GDF15 is elevated in many common metabolic states. Recent work shows that GDF15 rises most consistently when fatty acid availability exceeds mitochondrial and endoplasmic reticulum capacity. This review synthesizes emerging evidence that positions GDF15 as an endocrine sensor of lipid load rather than a general stress signal.
RECENT FINDINGS: Across acute dietary lipid exposure, endogenous lipolysis during fasting, chronic overnutrition, ketogenic feeding, and mitochondrial dysfunction, free fatty acids activate lipid-sensitive transcriptional pathways that induce GDF15 expression in kidney, liver, intestine, and adipose tissue macrophages. Once elevated, GDF15 engages hindbrain glial-cell-derived neurotrophic factor family receptor α-like (GFRAL) signaling to increase sympathetic outflow, promote whole-body fatty acid oxidation, redistribute lipid burden, and improve metabolic flexibility. These effects occur independently of reduced food intake and reflect coordinated actions across liver, adipose tissue, and skeletal muscle.
SUMMARY: Viewing GDF15 as a lipid-responsive hormonal signal reshapes our understanding of its physiological role and provides new insight into metabolic adaptations to lipid overload. This pattern suggests that GDF15 is part of a feedback system that attempts to match fatty acid oxidation with supply, analogous to how carbohydrate ingestion stimulates insulin to promote glucose oxidation and suppress hepatic glucose production to restore euglycemia. Within this framework, individual tissues respond in complementary ways to reduce lipid burden and maintain metabolic balance. Understanding this coordinated lipid-responsive network highlights opportunities to target the GDF15 pathway in disorders characterized by impaired fatty acid handling including obesity, type 2 diabetes, cardiovascular disease, cancer cachexia and metabolic dysfunction-associated steatotic liver disease (MASLD).

Keywords:  GFRAL; MASH; MASLD; adipose tissue; diabetes; fatty acids; growth differentiation factor-15; lipotoxicity; mitochondrial stress; triglycerides

DOI:  https://doi.org/10.1097/MOL.0000000000001025
NPJ Aging. 2026 Mar 05.

Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment.

Claudia Jara, Leslye Venegas-Zamora, Han S Park-Kang, Matías Lira, Micaela Ricca, Sebastian Valenzuela, Cheril Tapia-Rojas.

The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse hippocampal dysfunction by enhancing mitophagy and mitochondrial function. Two mouse models were used: 18-month-old C57BL/6 mice with established mitochondrial and cognitive deficits, and 5-month-old SAMP8 mice, an accelerated aging with cognitive decline starting from 6 months of age. UA was administered for 8 weeks, followed by assessments of ATP production, mitochondrial dynamics, mitophagy markers, synaptic proteins, and memory. In C57BL/6 mice, UA increased ATP, boosted proteins associated with fusion, antioxidant defense, and biogenesis, and reduced phosphorylated tau; however, these changes did not restore memory. In contrast, SAMP8 mice showed stronger effects: ATP rose sharply, mitochondrial stress and aberrant proteins decreased, and cognitive performance improved. These findings highlight UA effects as a preventive therapeutic agent, but are insufficient to reverse established cognitive decline, suggesting early mitophagy activation is critical to mitigate brain aging and neurodegeneration.

DOI: https://doi.org/10.1038/s41514-026-00351-3
J Biol Chem. 2026 Mar 04. pii: S0021-9258(26)00208-5. [Epub ahead of print] 111338

Chronic activation of p38α in skeletal muscle causes necrotic changes, but also abolishes expression of MK2, MK3 and MKK6 and the muscle recovers.

Nechama Gilad, Ilona Darlyuk-Saadon, Manju Payini Mohanam, David Engelberg.

  The MAPK p38α is associated with skeletal muscle's development, differentiation and functionality. But, as it is overactive in muscle diseases and aging, it was proposed to be a pivotal promoter of these processes as well. It is not clear how p38α is involved in these disparate activities, in particular whether its chronic activation alone is sufficient to cause them. We established a mouse model designed to study the effects of p38α per se in skeletal muscle. p38α activation is achieved by inducible expression, in muscle, of an intrinsically active variant, p38αD176A+F327S. Two weeks following expression muscle degeneration and necrotic changes were observed, accompanied with elevation of p53, caspase 3 and γH2AX; and, intriguingly, suppression of the p38's substrates MK2 and MK3 and its activator MKK6. At later timepoints the tissue recovered, apoptotic markers disappeared, but MK2, MK3 and MKK6 remained suppressed, perhaps as a response that restrains p38α-mediated damage and allows recovery. Induction of p38αD176A+F327S in young mice (2 months old) caused milder effects, but MK2, MK3 and MKK6 were suppressed. The p38αD176A+F327S effects were associated with altered level of ∼2,000 mRNA molecules. For 1,700 genes the effect was transient and for ∼300 constant. Stress-induced activation of p38α in C2C12 myoblasts was also associated with MK2 downregulation, but with constant elevation of apoptotic markers. Thus, chronic activation of p38α per se in skeletal muscle is sufficient to cause damage reminiscent of aging effects, but cannot impose full-scale and lasting aging phenotype. The tissue recovers while suppressing the p38α pathway.

Keywords:  C2C12 cells; MAPK; MK2; MK3; MKK6; p38α; skeletal muscle

DOI:  https://doi.org/10.1016/j.jbc.2026.111338
Brain. 2026 Feb 28. pii: awag083. [Epub ahead of print]

Constitutive neuronal expression and disease-associated upregulation of chitinases in amyotrophic lateral sclerosis.

Nayana Gaur, Christin Angerer, Zeynep I Gunes, Mihai Ancau, Mengzhe Wang, Henrick Riemenschneider, Charlene-Annett Hurler, Simon Mungwa, Patrick Lüningschrör, Anxhela Zhiti, Robert Steinbach, Michael Briese, Mugdha Srivastava, Mario Plaas, Andreas Hermann, Michael Sendtner, Sarah Jäkel, Dieter Edbauer, Jochen Herms, Sabine Liebscher, Julian Grosskreutz, Monika S Brill.

  Chitinases are hydrolytic enzymes responsible for degrading chitin and have been evolutionarily conserved across various species. Although their signaling pathways are not fully understood, the chitinases are considered active immunomodulators across several cell types. Specific isoforms, including Chitotriosidase-1 (CHIT1), Chitinase-3-like protein 1 (CHI3L1), and human-specific Chitinase-3-like protein 2 (CHI3L2), have emerged as markers of inflammation across the neurodegenerative spectrum, including amyotrophic lateral sclerosis (ALS). ALS is a fatal neuromuscular condition, and therapeutic development has been severely hindered by phenotypic heterogeneity and an incomplete understanding of etiology. Although several overlapping disease mechanisms can contribute to neuronal death, inflammation can exacerbate pathology. Prior studies have reported that CHIT1, CHI3L1, and CHI3L2 levels are elevated in the cerebrospinal fluid (CSF) of ALS patients and associated with disease aggressiveness. Nevertheless, several open questions critical to our understanding of the chitinases' role in ALS disease burden remain: namely, 1) which cell types in the central nervous system (CNS) are chitinase sources under physiological conditions, 2) which of these display chitinase upregulation in ALS, and 3) what is the diagnostic utility of the chitinases relative to established biomarkers. Here, we utilize pre-clinical models and post-mortem human tissue to demonstrate at both the transcriptomic and protein level that neurons are a primary source of chitinases; furthermore, neuronal chitinase expression is conserved across species. Under physiological conditions, CHI3L1 is more abundant and widely expressed across various cell types, whereas CHIT1 is predominantly expressed in neurons. Additionally, utilizing symptomatic mice from three familial ALS models, we demonstrate isoform-specific expression profiles, with astroglial and microglial upregulation of CHI3L1, and neuronal and microglial upregulation of CHIT1. Differing expression dynamics and diagnostic utility were also noted in our clinical cohort: CSF CHIT1 and CHI3L2 levels had more discriminatory power when distinguishing between ALS vs. non-ALS controls, while CHI3L1 was more closely associated with inflammation and aging across the neurodegenerative spectrum. Although the chitinases did not diagnostically outperform the neurofilament proteins as biomarkers, we propose that appreciating their expression patterns can aid in optimizing biomarker-guided trial design. Taken together, we demonstrate that chitinase upregulation in ALS is evident in various CNS cell types and that its neuronal expression may provide new insights into its role in disease activity.

Keywords:  CHI3L1; CHI3L2; CHIT1; amyotrophic lateral sclerosis; chitinase; neuron

DOI:  https://doi.org/10.1093/brain/awag083
Cell Metab. 2026 Mar 03. pii: S1550-4131(26)00048-3. [Epub ahead of print]

The S100A8/A9 complex promotes food intake and prevents adipose tissue loss during cancer cachexia in mice.

Lin Gao, Ying Liu, Ying Yu, Yingga Wu, Huanan Zhang, Cui Wang, Xinrui Gao, Yang Chen, Tingjie Zhang, Sixian Huang, Zhonghui Zhang, Zengguang Jin, Jie Chen, Haiyang Jing, Dehuang Kong, Yanlin Tian, Jacques Togo, Yong Lei, Yi Huang, Fan Xia, Min Li, Anyongqi Wang, Chao Jia, Sumei Hu, Di Chen, Xina Xie, Lu Wang, Jie Liu, Xiaomeng Wu, Changyong Tang, Chaoqun Niu, Zesong Li, John R Speakman.

  Cancer cachexia is a wasting syndrome characterized by reduced food intake and lean and fat tissue loss. In mice, cancer cachexia involved marked reductions in host fat and lean mass (particularly skeletal muscle), which were balanced by tumor growth. Using 15N tracing, the tumor gets protein (nitrogen) from both food intake and host tissue breakdown. Total energy expenditure remained unchanged due to metabolic compensation among the tumor, brown adipose tissue (BAT), and other organs, a phenomenon also observed in people with cancer. The decrease in leptin caused by fat loss did not stimulate food intake or reduce energy expenditure. We show that S100 calcium-binding protein A8 and A9 (S100A8/A9) and complement 3 (C3) in the hypothalamus play a key role in the reduction of food intake and fat mass during cancer cachexia. The peripheral administration of S100A8/A9 inhibitors and the hypothalamic knockdown of C3 significantly increased food intake and partially rescued fat and lean tissue loss.

Keywords:  C3; S100A8/A9; cancer cachexia; energy balance; fat loss; food intake; mice; muscle loss

DOI:  https://doi.org/10.1016/j.cmet.2026.02.005
Curr Opin Cell Biol. 2026 Mar 05. pii: S0955-0674(26)00015-3. [Epub ahead of print]100 102627

Neighbors who talk: Mitochondria-lysosome crosstalk in homeostasis.

Akriti Prashar, Rosa Puertollano.

Mitochondria are highly dynamic and multifaceted organelles that perform essential cellular functions such as producing energy, regulating metabolism, and orchestrating immune responses. Lysosomes are crucial signaling hubs that are important for nutrient sensing, signal transduction, and regulation of cellular degradation and recycling processes including the removal of damaged mitochondrial components or entire mitochondria. Together, these two organelles perform critical cellular functions. Emerging evidence links defects in both organelles to multiple diseases, underscoring how their functions are intricately linked. To coordinate their activities, mitochondria and lysosomes engage in bidirectional crosstalk, enabling reciprocal regulation of their respective functions. These 'organelle conversations' can occur through direct interactions at membrane contact sites where both organelles physically interact via stabilization by molecular tethers, or at a distance through signaling pathways. Here we discuss recent progress in our understanding of the mechanisms underlying mitochondria-lysosome crosstalk and how this communication is altered in pathological conditions.

DOI: https://doi.org/10.1016/j.ceb.2026.102627