bims-musmir 2025-10-05 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–10–05
ten papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Sex-specific survival but not tissue wasting in the KPP mouse model of pancreatic cancer-induced cachexia.
Muscle Abnormalities in Nonhospitalised Patients With Post-COVID-19 Condition.
Cachexia progression differs among mouse models of metastatic triple-negative breast cancer.
Temporal dynamics and functional implications of MiRNAs in denervation-induced skeletal muscle atrophy.
Longitudinal changes in muscle mass after ICU discharge: A prospective observational cohort study.
Atlas of Lysosomal Aging Reveals a Molecular Clock of Storage Disorder-Associated Metabolites.
Cachexia in mice blunts improved cognitive flexibility induced by calorie restriction.
Iron-sensitive RNA regulation by poly C-binding proteins.
Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models.
Selective inhibition of mitochondrial Kv1.3 prevents and alleviates multiple sclerosis in vivo.

J Appl Physiol (1985). 2025 Sep 30.

Sex-specific survival but not tissue wasting in the KPP mouse model of pancreatic cancer-induced cachexia.

Natalia M Weinzierl, Jayarani Putri, Kathryn M Spitler, Erin E Talbert.

  Cancer cachexia, a multifactorial condition resulting in muscle and adipose tissue wasting, reduces the quality of life of many people with cancer. Cachexia is highly prevalent in people with pancreatic ductal adenocarcinoma (PDAC), and many animal models of pancreatic cancer are used to understand mechanisms underlying cachexia. One such model is the KrasLSL-G12D, Ptf1aCre-ER/+, Ptenflox/flox (KPP) model, which utilizes an inducible Cre recombinase to initiate tumor development by tamoxifen administration. In our previous work, tumors were induced in KPP mice at 4 weeks of age. However, mice are rapidly growing at this age, and a portion of the body weight differences seen between control and KPP mice is likely due to slowed growth of KPP mice. In our current study, pancreatic tumors were induced to develop with tamoxifen in KPP mice after rapid postnatal growth has slowed at 10 weeks of age (KPP10). Given the expanding evidence of sexual dimorphisms in cancer cachexia, we utilized both male and female mice to assess potential sex differences. Similar to our previous findings, KPP10 mice had lower body, muscle, and adipose tissue weights compared to non-tumor mice, and these differences were similar between male and female mice. However, male mice experienced greater relative weight loss. Unexpectedly, we identified that survival was significantly shorter in female KPP10 mice compared to KPP10 males. Greater body weight at tumor induction was associated with longer survival, suggesting that the sex difference in survival may be related to differences in body weight between male and female mice.

Keywords:  Cachexia; development; mouse models; sexual dimorphism

DOI:  https://doi.org/10.1152/japplphysiol.00706.2025
J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70085

Muscle Abnormalities in Nonhospitalised Patients With Post-COVID-19 Condition.

Andrea Tryfonos, Gustav Jörnåker, Håkan Rundqvist, Kaveh Pourhamidi, Michael Melin, Helena Wallin, Filip J Larsen, Spyridon Pantelios, Anders P Mutvei, Veronika Tillander, Uwe J F Tietge, Sergio Perez Diaz, Douglas Crafoord, Alen Lovric, Rodrigo Fernandez-Gonzalo, Eric Rullman, Per Stål, Thomas Gustafsson, Helene Rundqvist, Tommy R Lundberg.

   BACKGROUND: Post-COVID condition (PCC) affects ~10% of SARS-CoV-2-infected individuals and manifests as persistent symptoms such as fatigue, exercise intolerance and muscle weakness. This study aimed to assess the skeletal muscle of these patients and compare them with healthy controls.
METHODS: Biopsies were obtained from the vastus lateralis muscle of 28 nonhospitalised PCC patients without concomitant diseases (75% women, mean age 46.4 ± 10.4 years) and 28 age- and sex-matched healthy controls (79% women, mean age 46.6 ± 8.7 years). The analysis included morphological and pathological alterations, fibre type composition, fibre cross-sectional area, capillarisation, number of myonuclei, presence of developmental myosin, CD68+ cells, macroautophagy markers, mitochondrial respiration, lipidomics and RNA sequencing.
RESULTS: PCC patients, compared to controls, had a higher percentage of angulated fibres (median [IQR] 0.43 [0.00-3.20] vs. 0.00 [0.00-0.00]; p < 0.001), small, rounded fibres (0.21 [0.00-1.20] vs. 0.00 [0.00-0.00]; p < 0.001) and fibres expressing fetal myosin (0.26 [0.00-1.15] vs. 0.00 [0.00-0.17]; p = 0.015). Semiquantitative analysis showed nuclear clumps (18/27, 66.6%), hypertrophic fibres (9/27, 33.3%) and fibrosis (22/27, 81.4%) in PCC patients. Fibre cross-sectional area was significantly lower in PCC patients (4031 ± 1365 vs. 4982 ± 1463 μm2; p = 0.018), largely driven by differences in type 2 fibre size (3533 ± 1249 vs. 4275 ± 1646 μm2; p = 0.068) than type 1 fibre size (4553 ± 1422 vs. 4932 ± 1380 μm2; p = 0.325). There was a significantly lower number of myonuclei per fibre in PCC (3.4 ± 1.1 vs. 4.1 ± 1.0; p = 0.012), but no difference in the presence of CD68+ per fibre (0.28 ± 0.15 vs. 0.22 ± 1.0; p = 0.115). No group differences were observed in macroautophagy markers LC3B (0.0032 ± 0.0007 vs. 0.0030 ± 0.0006; p = 0.232) or p62 (0.0072 ± 0.0023 vs. 0.0079 ± 0.0016; p = 0.814). Capillary-to-fibre ratio in PCC patients was lower for both type 1 (2.2 ± 0.7 vs. 2.6 ± 0.9; p = 0.044) and type 2 fibres (1.8 ± 0.6, vs. 2.2 ± 0.8; p = 0.022). Mitochondrial respiration was 11-28% lower in PCC patients, although not statistically significant. Lipidomics showed a lower number of phospholipids, and RNA sequencing revealed downregulation of eight metabolic pathways, primarily related to oxidative phosphorylation in PCC patients compared to controls (FDR < 0.05).
CONCLUSIONS: Nonhospitalised patients with PCC show signs of morphological and pathological muscle changes suggestive of degeneration and regeneration. The smaller overall fibre size, lower number of phospholipids, reduced mitochondrial oxidative capacity and lower capillarisation in these patients may be a consequence of reduced physical activity levels. The presence of clusters of atrophied angular and round-shaped fibres, signs of inflammation and fibrosis and increased expression of fetal myosin may reflect myopathic and neurogenic post-viral effects.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05445830.

Keywords:  RNA sequencing; muscle abnormalities; muscle histology; myopathies; post–COVID‐19 condition; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.70085
Am J Physiol Cell Physiol. 2025 Oct 03.

Cachexia progression differs among mouse models of metastatic triple-negative breast cancer.

Alastair A E Saunders, Chris Karagiannis, Wayne X Du, Lauren S James, Rachel E Thomson, Robin L Anderson, Paul Gregorevic.

  Cancer-associated cachexia decreases quality of life, reduces therapy response, and diminishes survival prospects. Effective cachexia countermeasures remain a significant unmet need. Research into cancer cachexia has made extensive use of models of colon, lung and pancreatic cancers. However, while cachexia also affects people with metastatic breast cancer, the mechanisms underlying breast cancer-associated cachexia are relatively understudied. Thus, we sought to investigate orthotopic mouse models of metastatic breast cancer for the progression of cachexia, with a focus on muscle wasting given its role in the frailty that is a hallmark of the condition. Female Balb/c mice received an intramammary fat pad injection of 4T1.2 or EMT6.5 cells, and NSG mice received MDA-MB-231-HM (231-HM) cells, to induce primary breast tumors that were subsequently excised. The resultant metastatic burden after approximately 4 weeks led to variable loss of muscle mass (tibialis anterior: EMT6.5: -17.1%, 231-HM: -13.5%, 4T1.2: -9.5%) and fat mass (gonadal fat: EMT6.5: -75.1%, 231-HM: -62.5%, 4T1.2: -30.2%). Muscle protein synthesis markers were decreased in EMT6.5 tumor-bearing mice. Distinct increases in the abundance of mRNA for E3-ubiquitin ligase and autophagy-related genes were observed between models. Neuromuscular junction perturbations were observed in EMT6.5 and 4T1.2 tumor-bearing mice. Neutrophilia was noted in the muscles of EMT6.5 tumor-bearing mice. The findings show that muscle mass and function are reduced in mouse models of metastatic breast cancer. Further study of these models could provide useful insights with which to better understand the diversity of cachexia progression across different cancer types.

Keywords:  Breast cancer; cachexia; metastasis; neuromuscular junction; neutrophil

DOI:  https://doi.org/10.1152/ajpcell.00230.2025
Mol Biol Rep. 2025 Sep 29. 52(1): 964

Temporal dynamics and functional implications of MiRNAs in denervation-induced skeletal muscle atrophy.

Wei Li, Yuntian Shen, Hua Liu, Fei Xue, Jitai Zhang, Jia Yi, Xia Li, Leilei Gong, Xinlei Yao, Hualin Sun, Bingqian Chen, Jianwei Zhu.

   BACKGROUND: Peripheral nerve injury often leads to muscle atrophy and compromised functional recovery. Growing evidence underscores the critical role of microRNAs (miRNAs) as key epigenetic regulators in this degenerative process. However, most current studies are limited to isolated time points, leaving a gap in the systematic understanding of the temporal dynamics of miRNA expression and their regulatory networks during the initiation of muscle atrophy.
METHODS AND RESULTS: In this study, we employed small RNA sequencing to dynamically profile miRNA expression in the tibialis anterior muscle across a time series from 12 h to 28 days following denervation. Through differential expression analysis, functional enrichment, and construction of miRNA-mRNA interaction networks integrated with multi-dimensional bioinformatics approaches including GO and KEGG analyses, we identified 199 temporally differentially expressed miRNAs. A pronounced shift in miRNA expression was observed at day 3 post-injury. Functional annotation of target genes revealed an transition in regulatory emphasis from cytoskeletal remodeling toward energy metabolic imbalance. Within this core window of day 3, rno-miR-128-1-5p was found to regulate mitochondrial metabolism-related genes, and cooperated with rno-miR-296-3p in modulating tight junction pathways.
CONCLUSIONS: Our findings illustrate that a time-specific molecular regulatory network underpins the pathological progression of denervation-induced muscle atrophy. These insights offer novel targets for developing precise therapeutic strategies aligned with disease timeline.

Keywords:  Energy metabolism; MiRNA; Muscle atrophy; Peripheral nerve injury

DOI:  https://doi.org/10.1007/s11033-025-11057-2
Clin Nutr. 2025 Sep 18. pii: S0261-5614(25)00252-3. [Epub ahead of print]54 53-61

Longitudinal changes in muscle mass after ICU discharge: A prospective observational cohort study.

Martin Sundström Rehal, Cechael Sebghati Sparrfelt, Nicole Lajewska, Arabella Fischer, Kristina Kilsand, Johan Helleberg, Henrike Häbel, Olav Rooyackers.

   BACKGROUND: There is limited published data describing patterns of muscle wasting after critical illness. Muscle ultrasound is a practical method to monitor changes in muscle mass after Intensive Care Unit (ICU) discharge. The aim of this study was to investigate longitudinal changes in muscle mass after ICU discharge in a group of mixed medical-surgical ICU patients.
METHODS: Adult ICU patients (n = 42) with a minimum length of stay in ICU of 3 days were prospectively enrolled. Baseline measurements of quadriceps muscle layer thickness, Medical Research Council sum score, hand grip strength and indirect calorimetry were performed in conjunction with ICU discharge and repeated every 3-5 days until hospital discharge or up to 28 days. The primary outcome was change in muscle thickness over time. Secondary outcomes were changes in physical function. Outcomes were assessed using best-fit generalized linear mixed models according to the Akaike information criteria. Interactions between outcomes and relevant covariates were investigated for hypothesis-generating purposes.
RESULTS: In the best-fit crude analysis model, a small but statistically significant change in muscle thickness over time (p = 0.0475) was observed. In exploratory covariate analysis, there was a strong interaction between body weight, female sex, low nutritional intake and increased loss of muscle thickness. Assessments of physical function improved over time. Female sex and ICU length of stay were identified as potential predictors of impaired physical recovery.
CONCLUSIONS: In this cohort of adult ICU patients, we did not find a relevant group-level change in muscle mass after ICU discharge. However, patients with poor nutritional intake and female sex may be at greater risk of muscle wasting after intensive care. Further studies are warranted to investigate the relevance of post-ICU nutrition and gender on recovery of muscle mass after critical illness.
TRIAL REGISTRATION: This study was prospectively registered at ClinicalTrials.gov on 2022-09-02 (NCT05531305).

Keywords:  Critical illness; Indirect calorimetry; Intensive care; Muscle loss; Muscle ultrasound; Physical function

DOI:  https://doi.org/10.1016/j.clnu.2025.09.004
bioRxiv. 2025 Sep 26. pii: 2025.09.25.678303. [Epub ahead of print]

Atlas of Lysosomal Aging Reveals a Molecular Clock of Storage Disorder-Associated Metabolites.

Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.

Lysosomal dysfunction is a well-recognized feature of aging, yet its systematic molecular investigation remains limited. Here, we employ a suite of tools for rapid lysosomal isolation to construct a multi-tissue atlas of the metabolite changes that murine lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle and adipose accumulate glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders like Batten disease. Levels of these metabolites increase linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigates these changes in the heart but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction, uncover a metabolic lysosomal "aging clock," and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.
One-Sentence Summary: Aging in mice is tracked by a lysosomal "clock", where glycerophosphodiesters and cystine - metabolites causally linked to juvenile lysosomal storage disorders - gradually accumulate in lysosomes of the brain, heart, skeletal muscle and adipose tissue.

DOI: https://doi.org/10.1101/2025.09.25.678303
Brain Behav Immun. 2025 Sep 27. pii: S0889-1591(25)00365-4. [Epub ahead of print] 106123

Cachexia in mice blunts improved cognitive flexibility induced by calorie restriction.

Kyna Conn, Laura Milton, Alyssa Teoh, Priscila T Levi, Kelly L Walton, Zane B Andrews, Claire J Foldi, Sarah H Lockie.

  Approximately 50-80 % of cancer patients suffer from cachexia, a metabolic syndrome involving inflammation, appetite loss, and muscle and fat wasting. Another common co-morbidity of cancer patients is cognitive impairment, and clinical evidence suggests the incidence of cachexia is linked to more severe cognitive symptoms. Given the difficulty of studying changes in cognitive function in human cancer patients, we set out to examine key aspects of cognitive performance in a mouse model of pancreatic cancer (pancreatic ductal adenocarcinoma; PDAC) cachexia, using an in-cage operant device (Feeding Experimental Device version 3; FED3) and a reversal learning task. Performance on the operant reversal task was compared to two control groups without cancer: ad libitum fed, sham injected with phosphate buffered saline (PBS), calorie restricted (CR) to 90-95 % of original body weight to control for reduced food intake and weight loss in cachexia mice. Our PDAC model recapitulated features of cachexia, including anorexia, weight loss, muscle wastage and inflammation. CR mice performed significantly better on the reversal task than both PDAC and PBS mice, achieving significantly more reversals and greater pellet retrieval. There was no difference between PBS and PDAC groups. These results suggest that the weight and appetite loss that occurs during cancer is processed by the brain differently to weight loss that occurs as a result of calorie restriction, with PDAC mice not experiencing an increase in motivational drive for food in line with their falling body weight. To mimic the malaise experienced by the PDAC group, we dosed CR mice with LiCl. Low dose (150 mM) LiCl did not affect responding, however, high dose (300 mM) LiCl significantly reduced both number of active pokes and pellet retrieval. This indicates a sickness-induced devaluation of reward, a factor that may impact poor performance of this task in the PDAC group. We additionally examined exploratory and anxiety-like behaviour in PBS and PDAC groups using a battery of maze-based tests. We saw no significant differences in performance between groups in the elevated plus maze, open field or light/dark box, suggesting no elevations in baseline anxiety-like symptoms in this cachexia model. These results occurred in the face of significantly elevated levels of the pro-cachexia factors GDF15, Activin A and Activin B, indicating that elevated levels of these TGF-β family peptides are not sufficient to produce behavioural changes in these tests. Our results provide evidence for a specific impact of sickness state on cognitive flexibility during pancreatic cancer.

Keywords:  Behaviour; Cancer cachexia; Cognitive flexibility; Instrumental learning; LiCl; Malaise; Mouse model; Reversal learning

DOI:  https://doi.org/10.1016/j.bbi.2025.106123
Nucleic Acids Res. 2025 Sep 23. pii: gkaf942. [Epub ahead of print]53(18):

Iron-sensitive RNA regulation by poly C-binding proteins.

Grant A Goda, Kwame Forbes, Michael E Sullivan, Grace A Eramo, Conner Breen, Douglas F Porter, Paul A Khavari, Daniel Dominguez, Maria M Aleman.

Iron is essential for normal cellular function. Homeostatic responses to low iron availability have long been known to rely on posttranscriptional mechanisms. Poly C-binding proteins (PCBPs) are essential RNA-binding proteins that regulate alternative splicing (AS), translation, and RNA stability. They also serve as critical iron chaperones that manage intracellular iron flux. However, the impact of cellular iron levels on the PCBP-directed transcriptome has not been globally evaluated. We found broad transcriptome changes, including AS, in response to low iron availability consistent with numerous operant posttranscriptional mechanisms that sense iron. By comparing AS directed by PCBP1 and PCBP2 to the iron-sensitive transcriptome, we found genes with iron-sensitive PCBP-mediated splicing regulation. We also found that iron chelation-induced splicing changes were attenuated with knockdown of PCBPs. Further, we demonstrate that iron chelation or mutation of PCBP1 iron binding residues enhances PCBP1 RNA association. This work highlights widespread iron-sensitive RNA regulation and identifies PCBP1 and PCBP2 as critical splicing factors contributing to this response.

DOI: https://doi.org/10.1093/nar/gkaf942
Nat Neurosci. 2025 Oct 03.

Muscle-derived miR-126 regulates TDP-43 axonal local synthesis and NMJ integrity in ALS models.

Ariel Ionescu, Lior Ankol, Anand Ganapathy Subramaniam, Topaz Altman, Iddo Magen, Yahel Cohen, Yehuda Danino, Tal Gradus-Pery, Yoav Niv, Ori Bar Avi, Danielle Geller, Amjd Ibraheem, Ruilei Cheng, Noam Steinberg, Leenor Alfahel, Pauline Duc, Zeynep Ergul-Ulger, Doruk Arslan, Ersin Tan, Florence Rage, Nilo Riva, Angello Quattrini, Can Ebru Bekircan-Kurt, Adrian Israelson, Amir Dori, Eran Hornstein, Eran Perlson.

Amyotrophic lateral sclerosis (ALS) is characterized by neuromuscular junction (NMJ) disruption and neurodegeneration. Recent findings highlight a pivotal role for TAR DNA-binding protein 43 (TDP-43) in forming axonal pathological condensates and facilitating NMJ disruption through inhibition of local protein synthesis. However, the mechanisms that drive local TDP-43 accumulation remain unknown. Here we identify that the TDP-43 axonal accumulation in peripheral nerves of SOD1 patients and mice stems from its aberrant local synthesis. This is a non-cell-autonomous process driven by muscle-derived miR-126a-5p extracellular vesicles (EVs). Inhibiting muscle secretion of miR-126a-5p prompts presynaptic TDP-43 synthesis and accumulation, which disrupts axonal translation and causes NMJ degeneration. Introducing miR-126 to SOD1G93A mice, primary co-cultures and human induced pluripotent stem cell (iPSC)-derived co-cultures with ALS mutations exhibits neuroprotective effects and delays motor decline. These findings identify a transcellular communication axis between muscles and motor neurons that regulates axonal local synthesis and NMJ maintenance, offering insights into ALS onset and progression.

DOI: https://doi.org/10.1038/s41593-025-02062-6
EMBO Mol Med. 2025 Sep 29.

Selective inhibition of mitochondrial Kv1.3 prevents and alleviates multiple sclerosis in vivo.

Beatrice Angi, Tatiana Varanita, Marco Puthenparampil, Valentina Scattolini, Michael Donadon, Mitra Tavakoli, Marta Favero, Maguie El Boustani, Matthias Soddemann, Lucia Biasutto, Diletta Arcidiacono, Alberto Ongaro, Andrea Mattarei, Livio Trentin, Gregory Wilson, Erich Gulbins, Paolo Gallo, Ildiko Szabo.

  Multiple sclerosis (MS) is characterized by invasion of the brain by effector memory T (TEM) lymphocytes that have been activated by repeated auto-antigen stimulation. Existing therapies target these and other autoreactive lymphocytes but their side effects include general immunosuppression and toxicity. Because the Kv1.3 potassium channel is highly expressed by chronically activated autoreactive TEMs, we investigated whether specific targeting of mitochondrial Kv1.3 using the pharmacological inhibitor PAPTP could selectively kill these TEMs in patients and mice with MS. 1 µM PAPTP targeted and reduced the number of autoreactive TEMs in blood samples from relapsing-remitting MS (RRMS) patients, leaving other T cell populations unaffected. Remarkably, pre-treatment of the entire T cell population with PAPTP during adoptive transfer of experimental autoimmune encephalomyelitis (EAE) killed TEMs and completely prevented disease onset in this mouse model. Moreover, PAPTP selectively eliminated activated TEMs and halted EAE progression when administered following disease onset. Our findings reveal the potential of PAPTP as an effective treatment for MS without adverse side effects.

Keywords:  Effector Memory T Cell; Experimental Autoimmune Encephalomyelitis; Mitochondrial Kv1.3 Channel Inhibition; Multiple Sclerosis

DOI:  https://doi.org/10.1038/s44321-025-00307-2