bims-musmir 2026-05-17 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–05–17
nine papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Inhibition of ceramide synthesis ameliorates body wasting in a cancer cachexia model.
Dietary supplementation with ursolic acid preserves skeletal muscle mass and strength in mouse models of cancer cachexia.
Differential Branched-Chain Amino Acid Metabolism in Tissues of Tumor-Bearing Male Mice.
Liver-derived ceramides link metabolism to tissue wasting in cancer cachexia.
GDF10 exacerbates metastatic burden and cachexia in murine models of cancer.
Tauroursodeoxycholic acid (TUDCA) ameliorates age-related skeletal muscle loss.
Sex differences in mitochondrial function in aging mouse skeletal muscle.
Distinct mitochondrial-derived vesicle pathways connect mitochondria with peroxisomes and lysosomes.
Protein-guided RNA barcoding links transcriptomes to synaptic architecture.

J Clin Invest. 2026 May 15. pii: e194687. [Epub ahead of print]136(10):

Inhibition of ceramide synthesis ameliorates body wasting in a cancer cachexia model.

Pauline Morigny, Honglei Ji, Laura Cussonneau, Sabrina Zorzato, Yun Kwon, Fabien Riols, Doris Kaltenecker, Alisa Maier, Vignesh Karthikaisamy, Samantha Corrà, Tanja Krauss, Claudine Seeliger, Syed Qaaifah Gillani, Joël J Tissink, Sandra Lacas-Gervais, Tuna Felix Samanci, Adriano Maida, Raul Terron-Exposito, Angela Trinca, Christine von Toerne, Leonardo Nogara, Melina Claussnitzer, Olga Prokopchuk, Jeannine Bachmann, Mauricio Berriel Diaz, Laure B Bindels, Ondrej Kuda, Hans Hauner, Mark Haid, Stephan Herzig, Carlo Fiore Viscomi, Jerome Gilleron, Anja Zeigerer, Bert Blaauw, Maria Rohm.

  Cachexia is a metabolic wasting syndrome affecting many patients with cancer, with poor survival outcomes. Disturbed lipid metabolism is a hallmark of cachexia, and our previous work has identified increased levels of circulating ceramides, which are bioactive lipids with adverse effects in metabolic diseases, as biomarkers for cachexia in mouse models and patients. Here, we investigated the role of ceramides on cachexia development using the well-established C26 colon carcinoma model. We demonstrated that elevated ceramides in cachexia arose from increased liver synthesis. We showed that ceramides directly contributed to impaired mitochondrial function and energy homeostasis in cachexia target tissues. Targeting ceramide synthesis using miRNA interference, or myriocin, an approved compound targeting the key synthesis enzyme serine palmitoyltransferase (SPT), improved markers of muscle atrophy in cachectic male mice. Importantly, we demonstrated that key enzymes involved in ceramide production were also elevated in livers, but not in other organs, of patients with cancer cachexia, correlating with disease severity. Our data place ceramides as contributors to metabolic dysfunction in cachexia and highlight the suitability of the ceramide synthesis pathway for therapeutic targeting.

Keywords:  Cancer; Lipidomics; Metabolism; Mitochondria; Oncology

DOI:  https://doi.org/10.1172/JCI194687
Am J Physiol Cell Physiol. 2026 May 12.

Dietary supplementation with ursolic acid preserves skeletal muscle mass and strength in mouse models of cancer cachexia.

Jeremy B Ducharme, Scott M Ebert, Miles E Cameron, Martin M Schonk, Chandler S Callaway, Andrew C D'Lugos, John J Talley, Sarah M Judge, Christopher M Adams, Andrew R Judge.

  Skeletal muscle atrophy is a devastating and defining feature of cancer cachexia that reduces quality of life, treatment tolerance, and survival, but cannot be prevented or reversed by current management strategies. Ursolic acid is a natural dietary compound that has been shown to inhibit atrophy-associated changes in skeletal muscle mRNA expression in rodents and dogs, leading to beneficial changes in skeletal muscle structure and function. We hypothesized that dietary supplementation with ursolic acid might help support skeletal muscle mass and function during cancer. To test this hypothesis, we investigated ursolic acid's effects in five in vivo mouse models of cancer cachexia that are driven by pancreatic, colon, and lung cancer cells of mouse and human origin. We found that dietary supplementation with ursolic acid has broad-spectrum effects towards cancer-induced skeletal muscle atrophy, significantly preserving muscle mass in all five cancer cachexia models. Ursolic acid's positive effects on muscle mass and muscle fiber size led to significant improvements in grip strength and muscle tetanic force, persisted in the presence of chemotherapy, and were not associated with discernable changes in food intake or tumor growth. Ursolic acid appeared to generate its beneficial effects in skeletal muscle by acting directly on muscle cells, inhibiting catabolic effects of tumor-derived secreted factors, and inhibiting > 90% of cancer-induced changes in skeletal muscle mRNA expression. These results strongly nominate ursolic acid as a promising potential nutritional approach for supporting muscle mass and function in individuals with cancer.

Keywords:  cancer cachexia; muscle atrophy; nutrition; skeletal muscle; ursolic acid

DOI:  https://doi.org/10.1152/ajpcell.00159.2026
Am J Physiol Regul Integr Comp Physiol. 2026 May 13.

Differential Branched-Chain Amino Acid Metabolism in Tissues of Tumor-Bearing Male Mice.

Miriam Zerrouk, Luca J Delfinis, Christopher G R Perry, Olasunkanmi A J Adegoke.

  Cancer cachexia is a multifactorial syndrome characterized by involuntary loss of skeletal muscle and adipose tissue that is often resistant to nutritional support. The branched-chain amino acids (BCAA: leucine, isoleucine, and valine) stimulate protein synthesis, yet BCAA-targeted therapies have yielded limited clinical benefit and inconsistent results. This might be related to altered metabolism of BCAA in cachexia. In this study, a C26 tumor allograft mouse model was used to examine how tumor burden alters BCAA metabolism across tumor tissue, liver, kidney, adipose tissue and skeletal muscle. Tumor tissue at 4 weeks exhibited higher BCAA levels and elevated branched-chain α-ketoacid dehydrogenase (BCKD) activity compared to samples collected at 2 weeks. At 4 weeks, skeletal muscles from tumor-bearing mice showed reduced BCAA concentrations relative to control. In contrast, liver and adipose tissue did not demonstrate uniform reductions in BCAA content, indicating tissue-specific metabolic responses. Multiple peripheral tissues also displayed lower expression of the L-type amino acid transporter 1 (LAT1) and alterations in downstream mechanistic target of rapamycin complex 1 (mTORC1) signaling. Notably, the soleus muscle maintained elevated phosphorylated S6 (P-S6) levels despite reduced BCAA availability, suggesting muscle-specific adaptations. These findings demonstrate distinct tumor and peripheral tissue alterations in BCAA handling in C26 tumor bearing mice. The observed changes in BCAA metabolism may underlie the limited success of BCAA-based interventions in cachexia and highlight the need for therapies that address both tumor and host metabolism.

Keywords:  Amino acid transporters; branched-chain amino acids; branched-chain α-keto acids; cancer cachexia; tissue metabolism

DOI:  https://doi.org/10.1152/ajpregu.00320.2025
J Clin Invest. 2026 May 15. pii: e206031. [Epub ahead of print]136(10):

Liver-derived ceramides link metabolism to tissue wasting in cancer cachexia.

Kerui Huang, Norbert Perrimon, Marcus D Goncalves.

Cancer cachexia, characterized by weight loss, muscle wasting, and anorexia, complicates cancer treatment and adversely affects patient outcomes. Both tumor-derived and host inflammatory factors are implicated in aspects of cachexia. The search for circulating mediators of cancer cachexia has focused largely on secreted proteins, but metabolites may also drive systemic wasting. In this issue, Morigny, Rohm, and colleagues identified the liver as a major source of circulating ceramides in cachectic mice and patients with cancer and demonstrated that inhibiting ceramide synthesis attenuated muscle wasting and preserved function in cachectic mice. These findings position the liver as an endocrine organ in cachexia and introduce a druggable metabolic pathway with translational potential.

DOI: https://doi.org/10.1172/JCI206031
Front Physiol. 2026 ;17 1773275

GDF10 exacerbates metastatic burden and cachexia in murine models of cancer.

Lauren S James, Alastair A E Saunders, Chris Karagiannis, Hongwei Qian, Robin L Anderson, Rachel E Thomson, Craig A Goodman, Paul Gregorevic.

  Metastasis and cancer-induced cachexia significantly reduce survivorship and quality of life for cancer patients. GDF10 (BMP3b) is a TGF-ß superfamily ligand with little knowledge of its role in cancer progression. Some studies have shown that GDF10 exerts tumor-suppressive effects in a range of cancer types and also plays a protective role against muscle wasting. Basal transcription of GDF10 was described previously to be downregulated in both primary tumors and cachectic muscle. Here, we set out to investigate the therapeutic potential of GDF10 in the 4T1.2 mouse model of breast cancer metastasis and in the C-26 mouse model of cancer cachexia, hypothesizing that GDF10 would ameliorate both metastatic and cachectic disease pathology. Systemic rAAV6:GDF10 administration to mice did not alter primary tumor growth; however, metastatic burden was increased in the mice bearing 4T1.2 tumors. Similarly, increased intramuscular rAAV6:GDF10 expression exacerbated skeletal muscle wasting in C-26 tumor-bearing mice. These results contradicted our initial hypothesis and highlight the complexity of signaling mechanisms utilized by BMP family ligands. Our data point to the need for more research to understand how to target GDF10 in anti-cancer therapy.

Keywords:  BMP3b; GDF10; adeno-associated virus; cachexia; cancer; metastasis; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2026.1773275
J Physiol. 2026 May 15.

Tauroursodeoxycholic acid (TUDCA) ameliorates age-related skeletal muscle loss.

Marina S Carvalho, Leticia Barssotti, Lohanna M B Dos Santos, Lucas R O Rosa, Maria Cristina C Gomes-Marcondes, Everardo M Carneiro, Helena C L Barbosa, Lucas Zangerolamo.

  Ageing leads to changes in body composition, including increased adiposity and reduced skeletal muscle mass and force. The alterations in ageing skeletal muscle result from impaired proteostasis driven by factors such as chronic inflammation, hormonal changes and reduced nutrient absorption. Those age-related changes in body composition and skeletal muscle compromise mobility and increase the risk of falls, fractures and metabolic disorders. Tauroursodeoxycholic acid (TUDCA), a bile acid with known benefits in chronic diseases, has been shown by our group to improve cognition and metabolic homeostasis in ageing and Alzheimer's disease mouse models. Interestingly, in previous studies, TUDCA treatment was also associated with increased skeletal muscle mass in ageing mice, leading us to hypothesize that TUDCA could target skeletal muscle to reduce age-related muscle loss. To explore this, we treated 18-month-old C57BL/6 mice with TUDCA or vehicle for 20 days, using 3-month-old mice as a young control group. We demonstrate that TUDCA treatment decreases body weight while increasing skeletal muscle mass, restores muscle fibre size and preserves functional integrity. Additionally, TUDCA enhances skeletal muscle insulin sensitivity through increased AKT activation and reduces tissue inflammation. Such improvements collectively support the restoration of skeletal muscle proteostasis, as indicated by increased protein synthesis and phosphorylation of key anabolic signalling pathways, including ribosomal protein S6 kinase beta-1 (P70S6K) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). These findings contribute to a better understanding of TUDCA's actions on skeletal muscles of ageing mice and highlight its role as a promising strategy against age-related muscle loss. KEY POINTS: Tauroursodeoxycholic acid (TUDCA) treatment attenuates skeletal muscle loss in ageing mice. TUDCA improves skeletal muscle insulin sensitivity and restores AKT signalling. TUDCA exerts an anti-inflammatory effect in skeletal muscle of ageing mice. TUDCA emerges as a potential therapy for age-related skeletal muscle loss.

Keywords:  ageing; ageing‐related skeletal muscle loss; bile acids; skeletal muscle; tauroursodeoxycholic acid

DOI:  https://doi.org/10.1113/JP290683
Front Aging. 2026 ;7 1824237

Sex differences in mitochondrial function in aging mouse skeletal muscle.

Angelina Holcom, Ashley Liao, Kaitlyn G Holden, Anne M Bronikowski, Ashley E Webb.

   Introduction: Sex differences in lifespan and age-associated phenotypes are pervasive across species, yet the mechanisms remain poorly understood. Mitochondrial dysfunction is a major hallmark of aging, but whether skeletal muscle mitochondria age along sex specific trajectories remains incompletely defined.
Methods: Here, we profiled mitochondrial bioenergetics and DNA integrity in flexor digitorum brevis (FDB) muscle from young (3-4 months) and aged (20-24 months) male and female C57BL/6 mice. We quantified cellular respiration in intact myofibers, measured mitochondrial DNA (mtDNA) copy number, and assessed expression of genes involved in mitochondrial dynamics, electron transport chain (ETC) function, and mtDNA maintenance.
Results: Cellular respiration differed by sex at baseline and changed with age in a sex-dependent manner. Aged females exhibited a lower basal and ATP-linked respiration than aged males. In contrast, spare respiratory capacity increased in aged females relative to aged males, consistent with age- and sex-specific remodeling of the bioenergetic reserve. mtDNA copy number increased with age in both sexes, with a greater increase in mtDNA content in aged males. Gene-expression analyses revealed age- and/or sex-dependent changes, including lower Pink1 expression in females compared to males, an age-related increase in the mtDNA maintenance gene Polg2 only in males, though most genes were not significantly different. As an exploratory systemic readout, we additionally assessed DNA damage responsiveness in whole-blood leukocytes using the alkaline comet assay following oxidative challenge; young females exhibited greater induced DNA damage than young males.
Discussion: Together, these data define sex- and age-associated mitochondrial remodeling in FDB and provide an initial assessment of sex-dependent inducible DNA damage responses in blood, underscoring the importance of sex as a biological variable in studies of aging.

Keywords:  alkaline comet assay; flexor digitorum brevis (FDB); mitochondria bioenergetics; mitochondrial DNA copy number; sex differences; skeletal muscle aging

DOI:  https://doi.org/10.3389/fragi.2026.1824237
Mitochondrion. 2026 May 12. pii: S1567-7249(26)00057-7. [Epub ahead of print]90 102167

Distinct mitochondrial-derived vesicle pathways connect mitochondria with peroxisomes and lysosomes.

Ayumu Sugiura, Kohta Nakamura, Heidi M McBride, Yasushi Okazaki.

  Mitochondrial-derived vesicles (MDVs) mediate selective trafficking of mitochondrial proteins and lipids to other organelles and contribute to organelle communication and mitochondrial quality control. While MDVs that deliver mitochondrial cargo to lysosomes have been extensively studied, the diversity of MDV pathways linking mitochondria to peroxisomes remains poorly understood. In particular, it is unclear how MDV pathways targeting peroxisomes relate to those delivering cargo to lysosomes, and whether cargos targeted to pre-existing peroxisomes utilize the same vesicular intermediates that participate in de novo peroxisome biogenesis. Here we examined MAPL trafficking using a peroxisome reconstitution system in PEX3-deficient fibroblasts. We found that MAPL is excluded from PEX3-positive pre-peroxisomal vesicles and instead is delivered to pre-existing peroxisomes, indicating that MAPL trafficking occurs through a pathway distinct from vesicles that initiate peroxisome formation. Structure-function analysis further revealed that a C-terminal amphipathic helix within MAPL is required for efficient targeting to peroxisomes. SNX9 depletion impaired both MAPL delivery to pre-existing peroxisomes and stress-induced lysosomal MDV pathways, whereas VPS35 depletion selectively reduced MAPL delivery without affecting lysosomal MDV pathways. In contrast, Parkin depletion impaired lysosomal MDV pathways but did not influence MAPL trafficking. Together, these findings demonstrate that mitochondria generate multiple classes of MDVs that are sorted into mechanistically distinct trafficking routes linking mitochondria with peroxisomes and lysosomes.

Keywords:  Lysosomes; Mitochondria; Mitochondrial-derived vesicles; Peroxisomes

DOI:  https://doi.org/10.1016/j.mito.2026.102167
bioRxiv. 2026 Feb 27. pii: 2026.02.26.705527. [Epub ahead of print]

Protein-guided RNA barcoding links transcriptomes to synaptic architecture.

Amanda Urke, Michael-John Dolan, Jonah Silverman, Michael Kim, Juan Pineda, Samantha Garcia, Judy Luu, Alex Buckley, Vipin Kumar, Binhui Zhao, Ken Chan, Naeem Nadaf, Karol S Balderrama, Don B Arnold, Beth Stevens, Benjamin E Deverman, Evan Z Macosko.

Mammalian brain function relies on the precise synaptic architecture of diverse cell types, yet scalable methods for linking a neuron's transcriptomic profile to its neuroanatomy remain limited. We present Synapse-seq, an in vivo strategy in which cell-identifying barcoded mRNAs are routed to subcellular compartments via targeting proteins and detected by single-cell and spatial genomics. Using AAV delivery for minimal perturbation of gene expression, we directed barcodes to presynaptic terminals (via synaptophysin) in four distinct circuits, or to postsynaptic sites (via nanobodies to endogenous PSD95) of hippocampal excitatory neurons. In the mouse primary visual cortex, presynaptic Synapse-seq recovered known long-range projections and discovered cortical layer subtypes with distinct thalamic innervation. In the anterior cortex, we elucidated simple topographic rules of corticostriatal innervation: intratelencephalic neurons followed a continuous depth-to-target gradient, while extratelencephalic neurons exhibited striatal collaterals that spatially correlated with medullary innervation. Finally, postsynaptic barcoding of excitatory neurons revealed cell type-specific variation in dendritic architectures across and within hippocampal subfields. These data establish Synapse-seq as a versatile, genomics-based approach for the integrated definition of molecular identity and synaptic organization across mammalian brains.

DOI: https://doi.org/10.64898/2026.02.26.705527