bims-musmir 2026-09-06 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–09–06
twelve papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia.
Impaired liver-muscle lactate metabolism causes sarcopenia via lactic acidosis in skeletal muscle in mice.
Matrix and intermembrane space-specific mitochondrial stress response in Alzheimer's disease.
An integrated reference atlas of human skeletal muscle.
How to Validate miRNA Targeting: Western Blot Analysis.
Detection of MicroRNAs Released from Argonautes.
isoTar: miRNA-Target Consensus Prediction with Enrichment Analysis for Canonical and Modified miRNAs.
Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.
Aβ-induced CaMKII hyperactivation is associated with impaired lysosomal maturation and mitophagy.
MicroRNAs and Their Profiling via Single-Cell Sequencing Technologies.
Preliminary miRNA profiling of plasma from patients infected with distinct SARS-CoV-2 variants.
RAB1 mediates OPTN-dependent mitophagy via ATG9A recruitment.

Cancer Discov. 2026 Sep 01. OF1-OF25

Tumor-Secreted ADAMTSL4 Activates Latent TGFβ1 to Drive Cancer Cachexia.

Juliano Machado, Vignesh Karthikaisamy, Hermine Mohr, Doris Kaltenecker, Pia Benedikt, Pauline Morigny, Amit Mhamane, Julia Geppert, Amy Rose Fumo, Kerstin Haase, Estefania Simoes, Joanna D C C Lima, Anastasia Georgiadi, Achim Krüger, José Pinhata Otoch, Marc E Martignoni, Vickie E Baracos, Mariam Jamal-Hanjani, Marilia C L Seelaender, Olga Prokopchuk, Julia Szendrödi, Maria Rohm, Stephan Herzig, Mauricio Berriel Diaz.

Cancer cachexia is a devastating wasting syndrome with no approved therapies. In this study, we identify the tumor-derived glycoprotein ADAMTSL4 as a circulating factor associated with body weight loss in preclinical cachexia models and patients with colorectal and lung cancers. In mice, Adamtsl4 overexpression converted non-cachexia-inducing tumors into cachexia-inducing tumors, whereas its deletion in cachexia-inducing tumors spared fat and muscle, blunted muscle atrophy signatures, and reduced cachexia severity. ADAMTSL4 engages the latency-associated peptide (LAP) of TGFβ1, promoting local activation of TGFβ1 at muscle cell membranes. Genetic blockade of proTGFβ1 or pharmacologic inhibition of TGFβ signaling reduced ADAMTSL4-dependent wasting in adipocytes and muscle cells. Suppression of tumor-derived ADAMTSL4 attenuated skeletal muscle fibrosis in mice. Together, the association between increased circulating ADAMTSL4 levels and TGFβ-driven muscle atrophy and fibrosis gene signatures in patients with cachectic cancer identifies ADAMTSL4 as an upstream regulator of TGFβ1 and a potential therapeutic target in cancer cachexia.
SIGNIFICANCE: Cancer cachexia lacks effective therapies and remains a major cause of cancer-related morbidity and mortality. We identify tumor-derived ADAMTSL4 as an upstream regulator of latent TGFβ activation via LAP engagement that promotes multiorgan wasting and fibrosis-related remodeling. Targeting ADAMTSL4 may provide a selective therapeutic strategy without systemic TGFβ pathway blockade.

DOI: https://doi.org/10.1158/2159-8290.CD-26-0045
Sci Adv. 2026 Sep 04. 12(36): eaeb4011

Impaired liver-muscle lactate metabolism causes sarcopenia via lactic acidosis in skeletal muscle in mice.

Takahiro Eguchi, Nozomi Hayashiji, Sho Tabata, Keiko Kabetani, Yasunori Shintani, Hideki Makinoshima, Naoki Ito.

Sarcopenia is a progressive disease characterized by age-related decline in skeletal muscle force and mass. The fundamental molecular pathogenesis of sarcopenia has not yet been elucidated. Here, we show that the accumulation of lactate and intracellular acidification, lactic acidosis, in skeletal muscle owing to impaired liver-skeletal muscle lactate metabolism is the fundamental cause of sarcopenia. Systemic lactate tolerance decreased in aged mice owing to the impaired lactate processing capacity in the liver, which caused lactic acidosis in skeletal muscle. Furthermore, pharmacological activation of hypoxia-inducible factor (HIF) or liver-specific activation of HIF1α improved age-associated impairment in lactate tolerance, lactic acidosis in skeletal muscle, and sarcopenia. Mechanistically, the decreased nicotinamide adenine dinucleotide level was the cause of dysregulated skeletal muscle functions due to lactic acidosis. Using mouse models, our results show lactic acidosis in skeletal muscle as a key molecular pathogenesis of sarcopenia and highlight HIF1α in the liver as a pharmacological target for sarcopenia.

DOI: https://doi.org/10.1126/sciadv.aeb4011
NPJ Dement. 2026 ;2(1): 83

Matrix and intermembrane space-specific mitochondrial stress response in Alzheimer's disease.

Shatakshi Shukla, Devin Kolmetzky, Shanikumar Goyani, Kunal Samantaray, Anupriya Sinha, Philip A Kramer, Dhanendra Tomar, Pooja Jadiya.

  Alzheimer's disease (AD) lacks effective therapies, partly due to an incomplete understanding of mitochondrial dysfunction, a key driver of neurodegeneration. Mitochondria activate the unfolded protein response (UPRmt) to maintain proteostasis, but the roles of matrix- and intermembrane space (IMS)-associated stress responses in AD remain unclear. Here, we used human microglial-like cells expressing mutant amyloid precursor protein together with compartment-targeted mitochondrial proteotoxic stressors to investigate matrix (UPRmt-MM) and IMS (UPRmt-IMS) stress responses. RNA-seq revealed activation of mitochondrial stress pathways and suppression of synaptic and lipid signaling in AD-like cells. UPRmt-MM promoted robust immune activation, severe oxidative phosphorylation defects, increased mitochondrial reactive oxygen species, and cell death. In contrast, UPRmt-IMS preferentially induced interferon signaling and suppressed antioxidant pathways. Notably, suppression of ATF5-dependent UPRmt signaling rescued mitochondrial dysfunction and reduced Aβ release. Together, these findings demonstrate that matrix- and IMS-targeted mitochondrial stress elicit distinct microglial responses and identify mitochondrial proteostasis as a potential therapeutic target in AD.

Keywords:  Cell biology; Molecular biology; Neuroscience

DOI:  https://doi.org/10.1038/s44400-026-00137-0
EBioMedicine. 2026 Aug 31. pii: S2352-3964(26)00349-X. [Epub ahead of print]131 106465

An integrated reference atlas of human skeletal muscle.

Christopher Nelke, Franziska Babilon, Christina B Schroeter, Anne-Katrin Güttsches, Paula Quint, Karsten Krause, Gerd Meyer Zu Hörste, Benedikt Schoser, Jörg H W Distler, Sven G Meuth, Felix Kleefeld, Tobias Ruck.

   BACKGROUND: Single-cell and single-nucleus RNA sequencing have transformed our understanding of human skeletal muscle biology, yet reproducibility and cross-study comparison remain limited by the lack of a unified reference framework and consistent cell-type annotation.
METHODS: We systematically searched for scRNA-seq and snRNA-seq datasets from adult human skeletal muscle. Seven eligible studies were retrieved and harmonised. We benchmarked multiple integration strategies to construct a joint reference atlas and derived modality-aware marker panels. Selected findings were validated by immunofluorescence in muscle biopsies.
FINDINGS: We generated a harmonised atlas comprising 122,000 cells and 630,000 nuclei from 88 healthy individuals and resolved 17 major skeletal muscle cell populations, spanning mononuclear compartments and multinucleated myofibers. Cross-modality analysis identified tissue- and modality-aware marker panels and nominated both established and previously unrecognised markers. NOVA1 emerged as a selective marker of fibro-adipogenic progenitors and was validated at the transcript and protein levels. Focusing on myonuclei, pseudotime modelling reconstructed differentiation trajectories from quiescent muscle stem cells to mature type I and type II myofibers and revealed lineage-specific programs, including transient activation of protocadherin-γ genes during type I myofiber differentiation. We further provide an interactive web application for marker-based cell-type prediction using the reference atlas.
INTERPRETATION: This integrated reference atlas and accompanying annotation tool establish a standardised framework for human muscle transcriptomics, promoting consistent cell-type assignment and providing a baseline for future studies of muscle development, ageing, and disease.
FUNDING: Else Kröner-Fresenius-Stiftung and the German Research Foundation.

Keywords:  Atlas; Muscle; Reference; Single cell; Single nucleus; Transcriptomics

DOI:  https://doi.org/10.1016/j.ebiom.2026.106465
Methods Mol Biol. 2026 ;3056 279-292

How to Validate miRNA Targeting: Western Blot Analysis.

Roma Karna, Federica Calore.

  MicroRNAs (miRNAs) are non-coding RNA molecules, usually 19-22 nucleotides long, that modulate gene expression by binding to specific mRNA targets. This interaction involves both the translation process and the stability of the mRNAs, thereby affecting gene expression after transcription. Their regulatory activity is carried out by binding to complementary sequences on target mRNAs, usually at their 3' UTR level, and resulting in their degradation or inhibition of translation. Given their ability to modulate the expression of targeted molecules, miRNAs can act either as oncogenes or tumor suppressor genes in cancer cells. Aberrant miRNA expression can lead to irregular gene expression, contributing to cancer development. Changes in miRNA expression profiles have been documented across multiple cancer types and are linked to clinical factors, such as tumor progression, metastasis, and patient survival rates. Certain miRNAs have potential as diagnostic biomarkers for early cancer detection and can serve as prognostic markers to predict patient outcomes and response to treatments. This chapter outlines the experimental procedures for validating microRNA targets through Western blotting. Western blotting, a "gold-standard" technique for protein analysis, offers a reliable approach for validating the impact of miRNAs on their target genes by assessing protein expression levels [1]. This validation is essential for understanding the roles miRNAs play in health and disease.

Keywords:  Post-transcriptional regulation; Protein expression analysis; Western blotting; microRNA (miRNA)

DOI:  https://doi.org/10.1007/978-1-0716-5392-0_15
Methods Mol Biol. 2026 ;3051 155-165

Detection of MicroRNAs Released from Argonautes.

Ji Won Lee, Chang Hoon Shin, J Grayson Evans, Erick C Won, Je-Hyun Yoon, Kyung-Won Min.

  The Argonaute (AGO) family of proteins is fundamental to microRNA (miRNA)-mediated gene silencing, serving as the central component of the RNA-induced silencing complex (RISC) by forming direct and stable binding with mature miRNAs. While miRNA-AGO interactions are essential for controlling gene expression and closely linked to human disease, AGO-free mature miRNAs also contribute to fine-tuning gene expression regulation through direct interaction with RNA-binding proteins (RBPs). This chapter presents a detailed biochemical methodology to quantify single-stranded mature miRNAs dissociated from AGO2, providing an approach to studying miRNAs release mechanisms.

Keywords:  Argonautes; RNA-binding proteins (RBPs); Ribonucleoprotein complexes (RNPs); microRNAs; microRNAs release; qPCR

DOI:  https://doi.org/10.1007/978-1-0716-5372-2_9
Methods Mol Biol. 2026 ;3056 61-85

isoTar: miRNA-Target Consensus Prediction with Enrichment Analysis for Canonical and Modified miRNAs.

Sebastiano Di Bella, Francesco Orilio, Shaopeng Gu, Rosario Distefano, Junhao Liu, Miriam Gaggianesi, Rosario Nicola Brancaccio, Shaohong Feng, Alessandro Laganà, Mario Acunzo, Qin Ma, Giovanni Nigita.

  Over the past few decades, microRNAs (miRNAs) have gained significant attention for their role in regulating gene expression and their association with various diseases, including cancer. These small noncoding RNAs (sncRNAs) have been identified as crucial regulators of different biological functions. However, recent advancements in high-throughput sequencing technologies have revealed a more complex miRNAome, driven by phenomena such as RNA editing and isomiRs, which modify miRNA sequences. This increasing complexity has necessitated the development of new tools to analyze the miRNAome and better understand their biological roles. To address this challenge, isoTar was developed-a high-performance, web-based containerized application designed for miRNA consensus-targeting prediction and functional enrichment analyses. This chapter provides a comprehensive overview of isoTar ( https://ncrnaome.osumc.edu/isotar/ ), including benchmarks of its performance and a guide to its usage.

Keywords:  A-to-I RNA editing; Consensus prediction; Functional enrichment analysis; MicroRNA target prediction; isomiRs

DOI:  https://doi.org/10.1007/978-1-0716-5392-0_5
Proc Natl Acad Sci U S A. 2026 Sep 08. 123(36): e2531151123

Single-cell profiling of mitochondrial phenotyping-coupled mtDNA genotyping.

Zhengyang Zhang, Liwei Zhang, Peng An, Xu Zhang, Yi Xia, Yunlu Kang, Xiaoxia Chen, Rongrong Hua, Yinhua Zhu, Yanling Hao, Yuan Huang, Yongting Luo, Junjie Luo, Guisheng Wang.

  Simultaneously profiling mitochondrial DNA (mtDNA) heteroplasmy and phenotypic variability at the single-cell level remains a challenge due to the absence of integrated methods that map mitochondrial genotypes alongside their functional states. We introduce human single-cell mitochondrial phenotype-coupled mtDNA sequencing (scMPCDS), a platform that quantifies mtDNA mutations and heteroplasmy together with mitochondrial membrane potential and reactive oxygen species within individual cells. Unlike bulk sequencing or separate single-omics techniques, scMPCDS directly correlates mitochondrial genomic instability with functional outcomes. Using this approach, we demonstrate that DdCBE-mediated mtDNA editing induces cell-specific off-target mutations in the mitochondrial genome, which coincide with diverse phenotypic changes. Applying scMPCDS to HeLa cells and clear cell renal cell carcinoma tissues, we identify single-cell subpopulations exhibiting distinct mtDNA mutation burdens and altered bioenergetic profiles, implicating potential mitochondrial heterogeneity-driven tumor evolution. Overall, scMPCDS serves as a versatile tool to unravel mitochondrial genotype-phenotype relationships at the single-cell level in both normal and disease states, thereby advancing precise mitochondrial diagnostics and therapeutics.

Keywords:  cancer; mitochondrial phenotype; mtDNA editing; mtDNA heteroplasmy; single cell

DOI:  https://doi.org/10.1073/pnas.2531151123
Neurochem Int. 2026 Sep 01. pii: S0197-0186(26)00143-9. [Epub ahead of print]200 106252

Aβ-induced CaMKII hyperactivation is associated with impaired lysosomal maturation and mitophagy.

Eun Cheng Suh, Yul A Kim, Kyung Eun Lee, Eun-Mi Park.

  Alzheimer's disease (AD) is characterized by amyloid-β (Aβ)-associated synaptic failure, intracellular Ca2+ dysregulation, and progressive impairment of lysosome-dependent clearance pathways. Aβ induces sustained Ca2+ overload, resulting in pathological hyperactivation of CaMKII, which normally participates in the regulation of autophagy. However, whether CaMKII hyperactivation contributes to Aβ-induced late-stage autophagy-lysosomal dysfunction and mitophagy failure remains unclear. This study aimed to examine the effects of the CaMKII inhibitor KN93 in Aβ25-35-exposed rat organotypic hippocampal slice cultures (OHSCs, ex vivo model) and the mouse brain in vivo. The results showed that Aβ25-35 induced intracellular Ca2+ elevation, CaMKII hyperactivation, and marked accumulation of LC3-II and p62. Ultrastructural and biochemical analyses revealed impaired lysosomal maturation, defective autophagosome-lysosome coupling, and accumulation of autophagic vacuoles, consistent with a blockade of late-stage autophagic flux. Increased levels of immature cathepsin D and reduced colocalization of LC3 with lysosomal markers further supported compromised lysosomal competence. Damaged mitochondria were recruited to lysosomal compartments but failed to undergo effective degradation, indicating abortive mitophagy under Aβ25-35 exposure. KN93 attenuated Aβ25-35-induced defects in lysosomal protease maturation, autophagosome-lysosome fusion, and mitochondrial clearance in both the ex vivo OHSCs model and the in vivo mouse brain. KN93 also ameliorated cognitive impairment in Aβ25-35-exposed mice. Taken together, these findings indicate that CaMKII hyperactivation contributes to Aβ25-35-induced autophagy-lysosomal dysfunction and neuronal damage, and that pharmacological inhibition of CaMKII with KN93 restores intracellular degradative capacity and ameliorates cognitive impairment under Aβ stress.

Keywords:  Amyloid beta; Autophagic flux; CaMKII; Calcium dysregulation; Lysosomal dysfunction; Mitophagy

DOI:  https://doi.org/10.1016/j.neuint.2026.106252
Methods Mol Biol. 2026 ;3056 249-264

MicroRNAs and Their Profiling via Single-Cell Sequencing Technologies.

Chinmayee Goda, Shaopeng Gu, Anjun Ma, Mario Acunzo, Giulia Romano, Adrienne M Dorrance, Ramiro Garzon, Qin Ma, Giovanni Nigita.

  MicroRNAs (miRNAs) are small non-coding RNAs that play essential roles in gene regulation, cellular function, and disease pathogenesis. Advances in single-cell RNA sequencing technologies have enabled the profiling of miRNAs at single-cell resolution, providing unprecedented insight into cell-specific regulatory networks and heterogeneity. This chapter presents an overview of miRNA biology, technical approaches for single-cell miRNA sequencing, and recent bioinformatics tools developed for data analysis. We discuss challenges in library preparation, such as adapter biases and low RNA input, and highlight integrative strategies for co-profiling miRNAs with other omics layers. Finally, we outline in the conclusion the potential of single-cell miRNA profiling to contribute to precision medicine and therapeutic development, including its possible use in biomarker discovery, monitoring tumor heterogeneity, and informing personalized treatment strategies. As the field progresses, continued innovation will be critical to overcoming existing barriers and fully harnessing the power of single-cell miRNA analyses.

Keywords:  miRNAs; ncRNAs; scRNA-seq

DOI:  https://doi.org/10.1007/978-1-0716-5392-0_13
Mol Biol Rep. 2026 Aug 29. pii: 1495. [Epub ahead of print]53(1):

Preliminary miRNA profiling of plasma from patients infected with distinct SARS-CoV-2 variants.

Ivana Baranova, Dana Dvorska, Andrea Kapinova, Dusan Brany, Marek Samec, Eva Baranovicova, Veronika Holubekova, Zuzana Kolkova, Maria Skerenova, Dusan Loderer, Elena Novakova, Erika Halasova, Peter Liptak, Peter Banovcin, Anna Bobcakova, Robert Rosolanka, Zuzana Dankova.

   BACKGROUND: Epigenetic regulation can play a dual role in viral infection, acting as part of the host defense, while being hijacked to control viral latency, replication, and persistence. During the COVID-19 pandemic, substantial evidence indicated that different SARS-CoV-2 variants may lead to distinct outcomes by affecting different molecular pathways, including epigenetic mechanisms.
METHODS AND RESULTS: In this study, we assessed miRNA expression using high-throughput microarray technology to simultaneously measure the expression of thousands of miRNAs. We focused on: comparing Delta and Omicron infections with healthy controls; identifying specific miRNAs linked to symptom severity; analyzing miRNA expression across different stages of Delta variant infection; and predicting miRNA target genes and evaluating miRNA-mRNA interactions. We identified 65 miRNAs that were significantly differentially expressed simultaneously in both SARS-CoV-2 variants compared to healthy samples. These miRNAs were categorized into distinct functional groups based on their roles in viral infection. We observed an association between the expression of specific miRNAs and virus-induced symptom severity and patients' outcomes in both variants. Furthermore, we examined miRNA expression across the various phases of the Delta variant and identified 38 miRNAs that were significantly differentially expressed. Finally, mRNA-miRNA interaction analysis revealed PTEN, IGF1R, MYC, and STAT3 as the most interacting genes.
CONCLUSION: Profiling thousands of miRNAs in response to different SARS-CoV-2 variants offers new opportunities for diagnosis, prognosis, and therapy. Although comorbidities and pathway cross-talk may influence the obtained results, our findings provide novel insights into the host response to SARS-CoV-2 infection at the epigenetic level.

Keywords:  COVID-19; SARS-CoV-2; miRNA; microarray analysis

DOI:  https://doi.org/10.1007/s11033-026-12632-x
Autophagy. 2026 Sep 01.

RAB1 mediates OPTN-dependent mitophagy via ATG9A recruitment.

Waka Kojima, Ryu Endo, Kei Okatsu, Hiroki Kinefuchi, Tomoko Tokita, Reika Kikuchi, Noriyuki Matsuda, Shuya Fukai, Koji Yamano.

  Damaged mitochondria are selectively eliminated through mitophagy, a critical quality control process. A kinase PINK1 and an E3 ubiquitin ligase PRKN/Parkin, both of which are mutated in familial Parkinson disease, amplify ubiquitin signals on the damaged mitochondria. The autophagy receptor OPTN plays a pivotal role in mitophagy by bridging ubiquitinated mitochondria with autophagy components. Although OPTN is known to recruit ATG9A-positive vesicles to facilitate mitophagy progression, the precise molecular mechanisms governing this recruitment remain poorly understood. In this study, we identify the small RAB GTPases RAB1A and RAB1B as direct binding partners of the OPTN leucine zipper (LZ) domain. We demonstrate that RAB1A/1B is required for the recruitment of ATG9A vesicles to mitochondria during the initial stages of mitophagy. Knockdown of RAB1A and RAB1B significantly impaired the assembly of OPTN at phagophore formation sites, leading to a profound inhibition of mitophagy progression. Mechanistically, we found that RAB1A/1B associate with ATG9A-positive vesicles via their C-terminal prenylation, thereby tethering these vesicles to the OPTN-bound mitochondria. Our findings establish a novel OPTN-RAB1-ATG9A axis that drives the de novo synthesis of phagophore membranes in close proximity to damaged mitochondria. This work clarifies how selective autophagy receptors spatially coordinate membrane trafficking to ensure the efficient clearance of dysfunctional organelles.

Keywords:  Autophagy; Optineurin; PINK1; Parkin; RAB GTPase; mitochondria; ubiquitin

DOI:  https://doi.org/10.1080/15548627.2026.2728346