bims-musmir 2025-09-07 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–09–07
thirteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Mitochondrial diagnostics reveal diffuse impairments in skeletal muscle energetics in aging mice.
Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.
Cancer Cachexia.
Skeletal muscle Rac1 mediates exercise training adaptations towards muscle glycogen resynthesis and protein synthesis.
Mitochondrial Biogenesis in Skeletal Muscle.
Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.
An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS.
Characterization of Muscle Tissue Cell Diversity and Clinical Implications in Idiopathic Inflammatory Myopathy.
C9orf72 ALS-causing mutations lead to mislocalization and aggregation of nucleoporin Nup107 into stress granules.
Combating muscle atrophy: emerging therapeutic targets that are fiber-type-specific.
Role of mTORC1 signaling in postnatal microglia activation preceding neurodegeneration in a mouse model for Niemann-Pick disease Type C.
MicroRNA-126-3p as a predictive biomarker for patients with primary biliary cholangitis refractory to ursodeoxycholic acid.
The microRNA miR-243 directs poly(UG) modification of a somatic mRNA in C. elegans.

J Appl Physiol (1985). 2025 Sep 04.

Mitochondrial diagnostics reveal diffuse impairments in skeletal muscle energetics in aging mice.

Keon D Wimberly, Mia Y Kawaida, Abigail L Tice, Xiaoping Luo, Jacob A Lackey, Samuel Alvarez, Lan Wei-LaPierre, Russell T Hepple, Terence E Ryan.

  Aging is associated with progressive declines in skeletal muscle mass, strength, and endurance, often linked to mitochondrial dysfunction. However, a complete understanding of mitochondrial impairments during aging is lacking. Herein, we examined how biological sex and aging affect muscle function and mitochondrial energy transduction. Methods: Male and female C57BL/6 mice at 16 and 26 months of age (N=48) were assessed for physical function, muscle contractility, histology, and mitochondrial bioenergetics. Using isolated limb muscle mitochondria, we employed a diagnostic approach to evaluate respiration, redox potential, and membrane polarization under physiologically relevant energy demands. Results: Aged mice had significantly lower grip strength (P = 2.7E-09), walking speed (P = 0.024), and endurance capacity (P = 1.24E-08). Muscle mass and contractile function were also significantly lower in 26-mo. old mice regardless of sex. Mitochondrial diagnostics revealed a significant reduction (30-50%) in oxygen consumption rates across a range of energy demands and substrate conditions in both male and female 26-mo. old mice. Redox and membrane potentials were also reduced (P < 0.05) in aged mice resulting in a lower respiratory efficiency when compared to 16-mo. old mice. Notably, aged males exhibited greater mitochondrial deficits with carbohydrate substrates, while aged females showed larger declines with fatty acid substrates. Conclusion: Aging induces diffuse impairments in mitochondrial energy transduction in skeletal muscle of mice of both sexes. The application of mitochondrial diagnostics platform offers new insights into the changes in muscle mitochondria with aging and could enhance the identification of interventions for preserving mitochondrial health in aging.

Keywords:  aging; metabolism; mitochondria; muscle

DOI:  https://doi.org/10.1152/japplphysiol.00601.2025
Adv Exp Med Biol. 2025 ;1478 343-363

Mitochondrial DNA Deletion Mutations: A Molecular Cause of Age-Induced Skeletal Muscle Fiber Dysfunction and Fiber Death Contributing to Sarcopenia.

Jonathan Wanagat, Robert Musci, Allen Herbst, Judd M Aiken.

  This chapter describes a molecular basis for age-induced muscle fiber loss involving the mammalian mitochondrial genome (mtDNA). Early studies of human mitochondrial myopathies, which display many phenotypes associated with muscle aging, led to the search for and subsequent discovery of similar genetic and histopathological changes in aging skeletal muscle. A diverse spectrum of mtDNA deletion mutations increase in abundance with age and clonally accumulate to high abundance within individual cells. Deletion accumulation results in a focal loss of electron transport and oxidative phosphorylation. These metabolic derangements activate apoptosis, leading to necrosis, fiber splitting, and eventual fiber loss. We have identified a number of interventions that are capable of modulating mtDNA deletion mutation frequency and the abundance of electron transport chain deficient fibers. Interestingly, in each case, the genetic and histological measures of mtDNA quality predict the lifespan effects of these interventions. We highlight the value of incorporating a geroscience view into the study of sarcopenia. The sequence of events from the deletion mutation of a single mtDNA molecule to muscle fiber death is not limited to skeletal muscle and has been observed in most other aging tissues, where these events likely contribute to cell loss.

Keywords:  Mitochondria; Mitochondrial DNA; Mutations; Sarcopenia

DOI:  https://doi.org/10.1007/978-3-031-88361-3_14
Adv Exp Med Biol. 2025 ;1478 285-314

Cancer Cachexia.

Melissa J Puppa, James A Carson.

  Skeletal muscle's metabolic and mechanical functions make it critical for maintaining human health, physical function, and quality of life in adults. The impact of skeletal muscle mass and the metabolic quality of muscle tissue becomes even more critical with advancing age and in patients with chronic diseases. To this end, cachexia is the involuntary loss of body weight, including muscle and fat loss, accompanying an underlying disease or condition. Cancer-induced cachexia occurs across many types of cancer and contributes to increased patient mortality, morbidity, and treatment toxicities, negatively impacting survival. Furthermore, there are currently no approved pharmacological treatments and limited evidence-based therapeutic options to prevent muscle loss or promote muscle recovery in cancer patients. While the systemic effects of cancer and subsequent treatment continue to be examined as drivers of overall wasting, the impact of skeletal muscle mass and metabolic quality in the cancer patient remains a critical area of investigation. A vital knowledge gap exists in understanding how maintaining muscle function and metabolic properties improves cancer patients' survival. The chapter explores the current understanding of how cancer and subsequent treatment impact skeletal muscle mass, function, and metabolic quality. To this end, the current understanding of systemic mediators and metabolic crosstalk between tissues that promote cancer-induced wasting is explored. Additional factors related to sex, physical activity level, chemotherapy-specific effects, and cancer heterogeneity are discussed concerning their impact on cancer-induced muscle wasting.

Keywords:  Cancer; Muscle atrophy; Wasting; Weight loss

DOI:  https://doi.org/10.1007/978-3-031-88361-3_12
Redox Biol. 2025 Aug 28. pii: S2213-2317(25)00357-X. [Epub ahead of print]86 103844

Skeletal muscle Rac1 mediates exercise training adaptations towards muscle glycogen resynthesis and protein synthesis.

Steffen H Raun, Carlos Henriquez-Olguín, Emma Frank, Farina Schlabs, Nanna Just Hahn, Jonas Roland Knudsen, Mona S Ali, Nicoline R Andersen, Lisbeth L V Møller, Jonathan Davey, Hongwei Qian, Ana Coelho, Christian S Carl, Christian T Voldstedlund, Bente Kiens, Rikard Holmdahl, Paul Gregorevic, Thomas E Jensen, Atul S Deshmukh, Erik A Richter, Lykke Sylow.

  Long-term exercise training elicits tremendous health benefits; however, the molecular understanding is incomplete and identifying therapeutic targets has been challenging. Rho GTPases are among the most regulated groups of proteins after exercise in human skeletal muscle, yet, unexplored candidates for mediating the effects of exercise training. We found that the Rho GTPase Rac1 was activated acutely after multiple exercise modalities in human skeletal muscle. Loss of Rac1 specifically in muscle attenuated contraction-induced muscle protein synthesis, diminished improvements in running capacity, and prevented muscle hypertrophy after exercise training in mice. Additionally, Ncf1∗ mice revealed that Rac1 regulated glycogen resynthesis via a NOX2-dependent mechanism. Molecularly, Rac1 was required for contraction-induced p38MAPK signaling towards HSP27, MNK1, and CREB phosphorylation. In vivo muscle-targeted overexpression of a hyperactive Rac1-mutant elevated reactive oxidant species production during exercise but did not affect muscle mass. Using mass spectrometry-based proteomics, we found that loss or gain of Rac1 muscle protein affected pathways related to cytoskeleton organization, muscle adaptation, and large ribosomal subunits. Thus, skeletal muscle Rac1 mediates both molecular and functional adaptation to exercise training.

Keywords:  Contraction; Exercise training; Glycogen; Metabolism; Muscle hypertrophy; Protein synthesis; Rac1; Skeletal muscle

DOI:  https://doi.org/10.1016/j.redox.2025.103844
Adv Exp Med Biol. 2025 ;1478 19-50

Mitochondrial Biogenesis in Skeletal Muscle.

David A Hood, Jonathan M Memme, Ashley N Oliveira, Neushaw Moradi, Sabrina Champsi.

  Mitochondrial biogenesis refers to the synthesis of nuclear- and mitochondrially encoded proteins, along with phospholipids, that aid in the expansion of the mitochondrial network. In skeletal muscle, mitochondria are organized as a reticulum, as this ideal morphology complements the elongated shape of a myofibre. This allows for efficient substrate diffusion and supports the vigorously dynamic metabolic capabilities of this tissue type. Mitochondria are central responders to deviations in metabolic homeostasis and are thus required to support acute or chronic bouts of endurance exercise, cold exposure, starvation, or other externally imposed stimuli. This chapter marks the introduction to skeletal muscle mitochondrial adaptability as we discuss the subcellular events that contribute to mitochondrial biogenesis. Topics range from mitochondrial content and subpopulations in different muscle fibre types to signaling cascades and regulatory elements that support this mechanism. The characterization of mitochondrial biogenesis was made possible through clever models of both exercise and muscle disuse, at times with genetic modifications to important regulators, and is incorporated in this discussion. The chapter concludes with reviews on changes to signaling towards biogenesis with age. Altogether, our review attempts to highlight the vast revelations on the targeting, contribution, and significance of mitochondrial biogenesis in skeletal muscle.

Keywords:  Aging; Calcium; Exercise signaling; Exercise training; Gene expression; Mitochondria; Mitochondrial dynamics; Muscle disuse; Protein import; ROS

DOI:  https://doi.org/10.1007/978-3-031-88361-3_2
bioRxiv. 2025 Aug 30. pii: 2025.05.19.654973. [Epub ahead of print]

Vitamin B12 supports skeletal muscle oxidative phosphorylation capacity in male mice.

Luisa F Castillo, Katarina E Heyden, Abigail R Williamson, Wenxia Ma, Olga V Malysheva, Nathaniel M Vacanti, Anna E Thalacker-Mercer, Martha S Field.

OBJECTIVES: Vitamin B12 plays a vital role in folate-mediated one-carbon metabolism (FOCM), a series of one-carbon transfer reactions that generate nucleotides (thymidylate (dTMP) and purines) and methionine. Inadequate levels of B12 impair FOCM, depressing de novo thymidylate (dTMP) synthesis, which in turn leads to uracil accumulation in DNA. This phenomenon has been well documented in nuclear DNA. Our previous work in liver tissue has shown that mitochondrial DNA (mtDNA) is more sensitive to FOCM impairments in that mtDNA exhibits elevated uracil levels before uracil concentrations in nuclear DNA change. However, the functional consequences of uracil accumulation in mtDNA are largely unknown. The purpose of this study was to determine how a functional B12 deficiency (induced by reduced levels of the B12-dependent enzyme methionine synthase (MTR)) and dietary B12 deficiency affects mtDNA integrity and mitochondrial function in energetic and mitochondria-rich tissues such as skeletal muscle.
METHODS: Male Mtr+/+ and Mtr+/- mice were weaned to either an AIN93G-based control (C) diet containing 25 μ/kg vitamin B12 or a B12-deficient (-B12) diet containing 0 μ/kg vitamin B12 to explore the effects of functional (Mtr+/-) and dietary B12 deficiency on muscle weight, uracil content in mtDNA, mtDNA content, and oxidative phosphorylation complex capacity in skeletal muscle. Aged (20-22mo) male C57BL6/N mice were acclimated to an AIN93G control diet four weeks, then received either weekly injections of saline (vehicle control [30 uL 0.9% NaCl]) or B12 (0.65mg per 30uL 0.9% NaCl) in each of two hindleg muscles [1.25 mg B12 total]) for 8 weeks.
RESULTS: The tibialis anterior (TA) muscle from Mtr+/- mice exhibited lowered maximal respiratory capacity of complex I, II, and IV of the electron transport chain than did TA from Mtr+/+ mice. Exposure to the -B12 diet lowered maximal capacity of complex I in red, mitochondrially rich muscle (soleus and mitochondria-rich portions of quadriceps and gastrocnemius) (p=0.02). Levels of uracil accumulation in mtDNA in red muscle and gastrocnemius were elevated ~10 fold with exposure to -B12 diet (p=0.04 and p<0.001, respectively). In aged mice gastrocnemius complex IV activity increased with intramuscular B12 supplementation (p=0.04).
CONCLUSIONS: Exposure to a B12-deficient diet led to uracil accumulation in mtDNA and impaired maximal oxidative capacity in two different types of skeletal muscle. B12 supplementation improved complex IV maximal capacity in gastrocnemius from aged mice.

DOI: https://doi.org/10.1101/2025.05.19.654973
bioRxiv. 2025 Aug 25. pii: 2025.08.21.671404. [Epub ahead of print]

An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS.

Olivia Gautier, Jacob A Blum, Thao P Nguyen, Sandy Klemm, Mai Yamakawa, Nasa Sinnott-Armstrong, Yi Zeng, Chung-Ha O Davis, Juliane Bombosch, Lisa Nakayama, Kevin A Guttenplan, Derek Chen, Arwa Kathira, Luke Zhao, Jessica E Rexach, William J Greenleaf, Aaron D Gitler.

To uncover molecular determinants of motor neuron degeneration and selective vulnerability in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons from the SOD1-G93A ALS mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a novel cell state we named 'disease-associated motor neurons' (DAMNs). We identified transcription factor regulatory networks that govern how healthy cells transition into DAMNs as well as those linked to vulnerable and resistant motor neuron subtypes. Using spatial transcriptomics, we found reactive glia located near motor neurons early in disease, suggesting early signaling events between motor neurons and glia. Finally, we found that the human orthologs of genomic regions with differential accessibility in SOD1-G93A alpha motor neurons are enriched for single nucleotide polymorphisms associated with human ALS, providing evidence that the genetic underpinnings of motor neuron vulnerability are conserved.

DOI: https://doi.org/10.1101/2025.08.21.671404
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70043

Characterization of Muscle Tissue Cell Diversity and Clinical Implications in Idiopathic Inflammatory Myopathy.

Honglin Zhu, Yizhi Xiao, Shasha Xie, Qiming Meng, Ting Ding, Ting Huang, Di Liu, Sijia Liu, Xiaoli Zhang, Huali Zhang, Hui Luo.

   BACKGROUND: Idiopathic inflammatory myopathies (IIMs) exhibit diverse cellular microenvironments in muscle tissues, yet the full spectrum of cell populations and changes remains unclear. This study aimed to characterize cellular heterogeneity, explore cell-cell interactions and assess the prognostic value of cell subtype abundances across IIM subtypes in Han Chinese.
METHODS: Muscle samples from six IIMs and three normal controls (NC) underwent single-cell RNA sequencing (scRNA-seq), whereas bulk RNA sequencing was performed on 203 IIMs and 19 NC. To avoid potential biases in cell proportion data from scRNA-seq, we used CIBERSORTx, a robust deconvolution method, to estimate cell subtype abundances in the large IIMs cohort. Cell-cell interaction, correlation and survival analysis were performed to investigate associations between cell subtypes, clinical features and disease progression.
RESULTS: We identified 10 T/NK cell types, eight monocyte/macrophage/dendritic cell types, 10 vascular-related cell types and four skeletal muscle cell types in IIM muscle tissues, with varying abundances across subgroups. Increased ISGhi T cells (1.42% vs. 0.075% in NC) and ISGhi monocytes (4.24% vs. 0% in NC) in dermatomyositis (DM), particularly in anti-MDA5 and anti-NXP2 patients, correlated with skin rashes and higher relapse rates. CD56dimCD16dimNK cells, exhibiting the highest cytotoxicity, were elevated most in anti-SRP (11.93% vs. 8.15% in NC) immune-mediated necrotizing myopathy (IMNM) and associated with severe muscle damage (p = 0.0001, rho = 0.267). Reduced angiogenesis-related SERPINB2+ monocytes (37.12% vs. 46.69% in NC) predicted better outcomes in IMNM (p = 0.006, HR = 0.264), whereas decreased HIF3A+CECs (14.29% in DM vs. 16.95% in NC), essential for endothelial barrier maintenance, negatively correlated with myofiber necrosis (p = 0.016, rho = -0.168) and were predictive of improved outcomes in DM (p = 0.014, HR = 0.412). Elevated endothelial-like pericytes in antisynthetase syndrome (ASS, 55.34% vs. 50.02% in NC) and IMNM (54.42%) were linked to muscle damage (p < 0.0001, rho = 0.272). Certain key pathways, such as angiogenesis-related pathways, were linked to better outcomes in DM (p = 0.002, HR = 0.405), whereas increased cytotoxicity scores, cell chemotaxis and regulation of inflammatory response were associated with a higher risk of relapse in both DM and IMNM. We also observed a reduction in Type I muscle fibres (22.66% in ASS vs. 66.68% in NC) that express MIF and MHC class I molecules and show extensive interactions with inflammatory cells via MIF-CD74 ligand-receptor signalling.
CONCLUSIONS: Our findings reveal significant shifts in cell subpopulations within IIM muscle tissues, which may contribute to muscle damage and influence disease outcomes.

Keywords:  cellular heterogeneity; disease outcome; idiopathic inflammatory myopathies; scRNA sequencing

DOI:  https://doi.org/10.1002/jcsm.70043
FEBS Lett. 2025 Sep 01.

C9orf72 ALS-causing mutations lead to mislocalization and aggregation of nucleoporin Nup107 into stress granules.

Saygın Bilican, Yara Nabawi, William Hongyu Zhang, Dunja Petrovic, Markus Wehrmann, Sara Muñoz-García, Seda Koyuncu, David Vilchez.

  Amyotrophic lateral sclerosis (ALS) is a fatal disorder caused by motor neuron degeneration. Hexanucleotide repeat expansions in the C9orf72 gene, the most common genetic cause of ALS (C9-ALS), drive toxicity through different mechanisms. These pathological changes include alterations in stress granules (SGs), ribonucleoprotein complexes formed under stress conditions. Here, we show that G3BP1, a core component of SGs, exhibits enhanced interaction with the nucleoporin Nup107 in motor neurons derived from patient iPSCs carrying C9orf72 mutations. Moreover, Nup107 colocalizes with SGs and aggregates in C9-ALS motor neurons. Notably, knockdown of npp-5, the Caenorhabditis elegans ortholog of Nup107, alleviates ALS-associated phenotypes in worm models, including reduced lifespan and impaired motility. Together, our findings provide insights into disease-related changes in C9-ALS pathogenesis.

Keywords:  Amyotrophic lateral sclerosis; C. elegans; Nucleoporins; Proteostasis; Stress granules; iPSC‐disease modeling

DOI:  https://doi.org/10.1002/1873-3468.70156
FEBS J. 2025 Aug 28.

Combating muscle atrophy: emerging therapeutic targets that are fiber-type-specific.

Samrat Chakraborty, Raz Ben-David, Shenhav Shemer.

  Skeletal muscle is essential for life as it enables physical movement, maintains posture, is crucial for breathing, and serves as a major site for energy and carbohydrate metabolism. Pathological conditions that reduce skeletal muscle mass and function-such as muscular dystrophies, motor-neuron diseases, cancer, type-2 diabetes, or aging-have detrimental effects on human health, reducing quality of life and survival. Currently, exercise is the only validated treatment for increasing muscle mass and function, but it is impractical for bedridden patients or the frail elderly. Significant advances in understanding the molecular mechanisms underlying atrophy of slow- or fast-twitch muscle fibers have identified numerous previously unknown key players that may show promise as potential drug targets. Here, we review these recent advances and discuss the potential of these discovered mechanisms as therapeutic targets to combat muscle wasting.

Keywords:  fiber type; muscle atrophy; myosin; skeletal muscle; therapeutic targets

DOI:  https://doi.org/10.1111/febs.70241
PLoS One. 2025 ;20(9): e0330437

Role of mTORC1 signaling in postnatal microglia activation preceding neurodegeneration in a mouse model for Niemann-Pick disease Type C.

Caroline E Murray, David S Betancourt-Trompa, Michael S Martinez, Julia M Carson, Lindsay J Walsh, Will C Remillard, Kayla B Fordyce, Rohan Reddy, Ileana Soto.

In Npc1 deficient mice, postnatal developmental alterations in cerebellar microglia and Purkinje cells (PCs) are followed by early-onset neurodegeneration. Even in the absence of PC loss, microglia in Npc1nmf164 mice display hallmark features of activation during early postnatal development, including increased proliferation, enhanced phagocytic activity, and morphological changes indicative of an activated state. In this study, we investigated whether mammalian target of rapamycin complex 1 (mTORC1) drives postnatal activation of cerebellar microglia in Npc1nmf164 mice. We found that elevated CLEC7A (Dectin-1) expression and phosphorylation of S6 ribosomal protein (pS6R), a downstream target of mTORC1, co-occurred in microglial precursors within the developing white matter region (dWMR) of wild-type (WT) mice at postnatal day 7 (P7), as well as in neurodegeneration-associated microglia located in the molecular layer (ML) of Npc1nmf164 mice at P60. In contrast, microglia in the WMR of Npc1nmf164 mice at P60 did not show evidence of CLEC7A expression or increased mTORC1 activation. Interestingly, microglial precursors in the dWMR of Npc1nmf164 mice did not exhibit increased mTORC1 activation at P7 but instead showed delayed increased activation at P10. Inhibiting mTORC1 signaling with rapamycin from P10 to P21 reduced both microglial proliferation and soma size in Npc1nmf164 mice. Additionally, rapamycin treatment preserved VGLUT2⁺ presynaptic terminals/axons that innervate PC dendrites and decreased the total volume of CD68⁺ phagosomes per microglial cell, suggesting a reduction in phagocytic activity. However, the volume of VGLUT2⁺ synaptic material per phagosome remained unchanged between vehicle- and rapamycin-treated groups. While rapamycin enhanced myelination in Npc1nmf164 mice, it did not alter microglial phenotypes in the cerebellar WMR, suggesting that mTORC1 signaling does not mediate WMR microglial activation in this model. Together, our findings demonstrate that mTORC1 activation contributes to the aberrant activation of postnatal ML microglia and to early cerebellar pathology in Npc1nmf164 mice.

DOI: https://doi.org/10.1371/journal.pone.0330437
World J Gastroenterol. 2025 Aug 21. 31(31): 109828

MicroRNA-126-3p as a predictive biomarker for patients with primary biliary cholangitis refractory to ursodeoxycholic acid.

Shi-Da Pan, Chu-Yue Xiong, Ying-Juan Shen, Jia-He Tian, Yi-Lin Wang, Jia-Ning Wang, Si-Yu Wang, Feng-Yi Li, Li-Feng Wang, Qin Qiu, Luo Yang, Xiao-Meng Liu, Jun-Qing Luan, Zheng-Sheng Zou, Fu-Sheng Wang, Fan-Ping Meng.

   BACKGROUND: Ursodeoxycholic acid (UDCA) is the first-line therapeutic agent for primary biliary cholangitis (PBC). However, a subset of patients exhibit a suboptimal response to UDCA, and reliable predictive biomarkers remain elusive. Studies have implicated plasma microRNAs (miRNAs) in the pathophysiological progression of PBC, with certain miRNAs demonstrating potential as diagnostic and disease progression biomarkers. However, biomarkers capable of predicting the therapeutic efficacy of UDCA have not yet been identified.
AIM: To investigate differentially expressed miRNAs in PBC patients with divergent UDCA treatment responses and to explore potential biomarkers that predict treatment response in PBC.
METHODS: Plasma samples from treatment-naive PBC patients receiving ≥ 1 year of standard UDCA treatment were collected. Efficacy was evaluated using the Paris I criteria. Patient samples were divided into discovery group (n = 10) and validation group (n = 30), with further stratification of patients into drug-resistant and drug-sensitive (DS) cohorts. Next-generation sequencing and quantitative real-time polymerase chain reaction were used to screen, functionally analyze, and validate the pre-treatment miRNA profiles of the treatment groups.
RESULTS: Forty-nine miRNAs were differentially expressed between the two groups before UDCA treatment (N = 40). MiR-22-5p and miR-126-3p were highly expressed in the DS group before treatment (P < 0.001), whereas miR-7706 exhibited a low expression (P = 0.017). Post-treatment, miR-126-3p maintained low expression in the drug-resistant group (P = 0.003), but showed elevated levels in the DS group (P < 0.001). Logistic regression analysis identified miR-126-3p expression (odds ratio = 34.32, 95% confidence interval: 1.95-605.40, P = 0.016) as a significant factor influencing UDCA treatment response, while miR-22-5p (P = 0.990) and miR-7706 (P = 0.157) showed no significant association. MiR-126-3p levels were negatively correlated with total bilirubin (r = -0.356, P = 0.005) and immunoglobulin G levels (r = -0.311, P = 0.015). The area under the receiver operating characteristic curve was 0.891 (P = 0.0003, 95% confidence interval: 0.772-1.000) with a sensitivity of 82.4% and a specificity of 84.6%.
CONCLUSION: Plasma miRNA expression profiles are heterogenous in patients with PBC with differential responses to UDCA therapy. MiR-126-3p demonstrates predictive potential for a suboptimal response to UDCA in patients with PBC.

Keywords:  Early prediction; Efficacy; MicroRNA; Primary biliary cholangitis; Ursodeoxycholic acid

DOI:  https://doi.org/10.3748/wjg.v31.i31.109828
MicroPubl Biol. 2025 ;2025

The microRNA miR-243 directs poly(UG) modification of a somatic mRNA in C. elegans.

David D Lowe, Martin Newman, Gary Ruvkun, Scott G Kennedy.

C. elegans RDE-3 adds poly UG tails to mRNAs targeted for silencing by the dsRNA-initiated RNA interference (RNAi) pathway. RDE-3 can also add p(UG) tails to some endogenous cellular mRNAs. Mechanisms directing RDE-3 to pUGylate specific mRNAs are not understood. Here we show that the miRNA miR-243 directs pUGylation of an intestine-specific mRNA y47h10a.5 , which leads to silencing of the mRNA. The data show that genome-encoded small regulatory RNAs are one mechanism by which RDE-3 can be directed to pUGylate specific mRNAs for gene regulation.

DOI: https://doi.org/10.17912/micropub.biology.001754