bims-musmir 2025-07-27 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–07–27
eight papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer.
B0092 tumor-bearing mice are a new model for the study of cachexia in head and neck cancer.
Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.
Mapping the metabolic perturbations associated with palmitate-induced oxidative stress and development of insulin resistance in skeletal muscle cells.
Using circular RNAs to target toxic RNA-binding proteins in amyotrophic lateral sclerosis.
Combined bulk and single-cell transcriptomic analysis reveals cell-type-specific inflammatory crosstalk in pancreatic cancer.
PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.
Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans.

Mol Metab. 2025 Jul 16. pii: S2212-8778(25)00118-8. [Epub ahead of print] 102211

Mitochondrial-targeted plastoquinone therapy prevents early onset muscle weakness that occurs before atrophy during ovarian cancer.

Luca J Delfinis, Shahrzad Khajehzadehshoushtar, Luke D Flewwelling, Nathaniel J Andrews, Madison C Garibotti, Shivam Gandhi, Aditya N Brahmbhatt, Brooke A Morris, Bianca Garlisi, Sylvia Lauks, Caroline Aitken, Leslie Ogilvie, Stavroula Tsitkanou, Jeremy A Simpson, Nicholas P Greene, Arthur J Cheng, Jim Petrik, Christopher G R Perry.

  Muscle loss with cancer causes weakness, worsens quality of life, and predicts reduced overall survival rates. Recently, muscle weakness was identified during early-stage cancer before atrophy develops. This discovery indicates that mechanisms independent of muscle loss must contribute to progressive weakness. While mitochondrial stress responses are associated with early-stage 'pre-cachexia' weakness, a causal relationship has not been established. Here, using a mouse model of metastatic ovarian cancer cachexia, we identified that the well-established mitochondrial-targeted plastoquinone SkQ1 partially prevents muscle weakness occurring before the development of atrophy in the diaphragm. Furthermore, SkQ1 improved force production during atrophy without preventing atrophy itself in the tibialis anterior and diaphragm. These findings indicate that atrophy-independent mechanisms of muscle weakness occur in different muscle types throughout ovarian cancer. Ovarian cancer reduced flexor digitorum brevis (FDB) whole muscle force production and myoplasmic free calcium ([Ca2+]i) during contraction in intact single muscle fibers, both of which were prevented by SkQ1. Remarkably, changes in mitochondrial reactive oxygen species and pyruvate metabolism were heterogeneous across time and between muscle types which highlights a considerable complexity in the relationships between mitochondria and muscle remodeling throughout ovarian cancer. These discoveries identify that muscle weakness can occur independent of atrophy throughout ovarian cancer in a manner that is linked to improved calcium handling. The findings also demonstrate that mitochondrial-targeted therapies exert a robust effect in preserving muscle force early during ovarian cancer during the pre-atrophy period and in late stages once cachexia has become severe.

Keywords:  Ovarian cancer cachexia; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1016/j.molmet.2025.102211
Am J Physiol Cell Physiol. 2025 Jul 21.

B0092 tumor-bearing mice are a new model for the study of cachexia in head and neck cancer.

Patrick D Livingston, Ana Luiza Labbate Bonaldo, Nicholas A Jamnick, Natalia M Weinzierl, Caleb J Gammon, Chandler S Callaway, Schuyler Lee, Bifeng Gao, Andrew Goodspeed, Robson F Carvalho, Christian D Young, David J Orlicky, Douglas J Adams, Leah J Novinger, Andrea Bonetto.

  Introduction: Head and neck cancer (HNC) accounts for ~4% of all cancers but causes ~15,000 deaths annually in the U.S. Over 40% of HNC patients present with cachexia, a severe comorbidity associated with skeletal muscle defects, worsened treatment response, and poor outcomes. The mechanisms behind HNC cachexia remain unclear, partly due to limited small animal models. This study characterizes functional and molecular features of cachexia in a novel preclinical model using tobacco-induced B0092 oral squamous cell carcinoma in C57BL/6J mice. Methods: C2C12 myotubes were exposed to various concentrations of B0092 conditioned media (CM) to assess effects on myotube diameter and expression of muscle-specific ubiquitin ligases (MuRF-1, Atrogin-1). C57BL/6J male and female mice were implanted with B0092 cells (5x105 cells) to investigate musculoskeletal effects of HNC. RNA sequencing of muscle identified gene signatures associated with cachexia. Results: Myotubes treated with B0092 CM showed atrophy already at 25% CM (-21%, p<0.01), along with elevated MuRF-1 (+81%, p<0.05) and Atrogin-1 (+27%, p<0.05). B0092 tumor growth in male mice led to muscle atrophy, reduced strength (-36%, p<0.001), and lower bone mineral density (-8%, p<0.01). Muscle atrophy correlated with increased MuRF-1 (+1.96-fold, p<0.05) and Atrogin-1 (+1.97-fold, p<0.05). Female mice exhibited moderate cachexia despite similar tumor size. RNA sequencing of muscle in male B0092 hosts revealed mitochondrial dysfunction and upregulation of proteasome- and translation-related pathways, supporting a shift toward protein degradation and impaired energy metabolism. Conclusion: These findings suggest that B0092-bearing mice are valuable to uncover novel molecular pathways and potential therapeutic targets for HNC cachexia.

Keywords:  bone loss; cachexia; head and neck cancer; muscle wasting; muscle weakness

DOI:  https://doi.org/10.1152/ajpcell.00374.2025
Cell. 2025 Jul 18. pii: S0092-8674(25)00741-X. [Epub ahead of print]

Functional liver genomics identifies hepatokines promoting wasting in cancer cachexia.

Doris Kaltenecker, Søren Fisker Schmidt, Peter Weber, Anne Loft, Pauline Morigny, Juliano Machado, Julia Geppert, Kerstin Beate Saul, Pia Benedikt, Claudia-Eveline Molocea, Rachel Scott, Kerstin Haase, Marc E Martignoni, Ana Jimena Alfaro, Kan Kau Chow, Estefania Simoes, José Pinhata Otoch, Joanna D C C Lima, Charles Swanton, Nadine Spielmann, Martin Hrabé de Angelis, Markus Elsner, Ali Ertürk, Kenneth A Dyar, Maria Rohm, Olga Prokopchuk, Mariam Jamal-Hanjani, Marilia Seelaender, Johannes Backs, Stephan Herzig, Mauricio Berriel Diaz.

  In cancer cachexia, the presence of a tumor triggers systemic metabolic disruption that leads to involuntary body weight loss and accelerated mortality in affected patients. Here, we conducted transcriptomic and epigenomic profiling of the liver in various weight-stable cancer and cancer cachexia models. An integrative multilevel analysis approach identified a distinct gene expression signature that included hepatocyte-secreted factors and the circadian clock component REV-ERBα as key modulator of hepatic transcriptional reprogramming in cancer cachexia. Notably, hepatocyte-specific genetic reconstitution of REV-ERBα in cachexia ameliorated peripheral tissue wasting. This improvement was associated with decreased levels of specific cachexia-controlled hepatocyte-secreted factors. These hepatokines promoted catabolism in multiple cell types and were elevated in cachectic cancer patients. Our findings reveal a mechanism by which the liver contributes to peripheral tissue wasting in cancer cachexia, offering perspectives for future therapeutic interventions.

Keywords:  INTACT; REV-ERB; adipose tissue wasting; cachexia; circadian clock; hepatic reprogramming; liver-secreted factors; muscle atrophy

DOI:  https://doi.org/10.1016/j.cell.2025.06.039
Biophys Chem. 2025 Jul 09. pii: S0301-4622(25)00102-4. [Epub ahead of print]326 107490

Mapping the metabolic perturbations associated with palmitate-induced oxidative stress and development of insulin resistance in skeletal muscle cells.

Shreyada N Save, Soumya S Sahoo, Kalyani Ananthamohan, Saleem Yousf, Pratishtha Singh, Osama Aazmi, Jeetender Chugh, Shilpy Sharma.

  The development of insulin resistance (IR) in the skeletal muscle has been identified as one of the hallmarks of Type 2 diabetes mellitus (T2DM). Studies have shown that palmitic acid (PA), a saturated free fatty acid (FFA), can contribute to the development of IR in various insulin-responsive tissues via the induction of oxidative stress and mitochondrial dysfunction. The specific molecular mechanisms and metabolic changes that lead to IR development are not completely defined, and a better understanding of these mechanisms is needed. Our study aims to identify metabolites linked with the development of IR in skeletal muscles using PA and map the major metabolic pathways involved. Rat-derived L6 myotubes were exposed to PA to establish IR. Cellular and biochemical experiments were performed, and the metabolic perturbations associated with the induction of oxidative stress and IR were identified using 1H NMR-based metabolomics. PA exposure was associated with a loss of cellular viability due to lipid accumulation in the myotubes. This was associated with an induction of oxidative stress, loss of function, and reduced mitochondrial membrane potential. The metabolic fingerprint linked with the development of oxidative stress and IR in skeletal muscles was identified, wherein significant perturbations in the levels of methanol, dimethylamine, serine, lysine, proline, glycerol, and alanine (p < 0.05) were observed. The dysregulated metabolites and pathways identified in this study can be proposed as biomarkers for detecting palmitate-induced oxidative stress and development of IR in the skeletal myotubes - phenotypes associated with T2DM and related metabolic disorders.

Keywords:  Insulin resistance; Metabolomic markers; Oxidative stress; Palmitic acid; Skeletal muscle cell; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.bpc.2025.107490
Mol Ther Methods Clin Dev. 2025 Sep 11. 33(3): 101525

Using circular RNAs to target toxic RNA-binding proteins in amyotrophic lateral sclerosis.

Anne Kruse Hollensen, Matilde Helbo Sørensen, Sofie Vesterbæk Thomsen, Henriette Sylvain Thomsen, Christian Kroun Damgaard.

  Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration and is in many cases associated with mutations in genes encoding RNA-binding proteins (RBPs), including fused in sarcoma (FUS) and heterogeneous nuclear ribonuclearprotein A1 (hnRNPA1). These mutations often cause cytoplasmic mislocalization and aggregation of these typically nuclear proteins. Current treatment options for ALS are limited, highlighting the need for new therapeutic strategies. Here, we demonstrate an approach using circular RNAs (circRNAs) to target disease-associated RBPs for degradation. We designed circRNAs containing binding sites for both the target RBPs (FUS or hnRNPA1) and ring finger and CCCH-type domains 2 (RC3H2), an RNA-binding E3 ubiquitin ligase. Through RNA immunoprecipitations and protein analyses, we show that these circRNAs can form ternary complexes with their target RBPs and RC3H2. Importantly, we observed significant reductions in steady-state protein levels of ALS-associated FUS-P525L (20%) and hnRNPA1-P288S (30%) mutants when treated with their respective targeting circRNAs. These findings provide proof of concept for using circRNAs as scaffolds to promote the degradation of disease-associated RBPs, establishing a foundation for developing advanced RNA-based therapeutic strategies for ALS and potentially other RBP-related diseases.

Keywords:  ALS; E3 ubiquitin ligase RC3H2; FUS; circRNA PROTAC; disease-causing RBPs; hnRNPA1

DOI:  https://doi.org/10.1016/j.omtm.2025.101525
Clin Exp Med. 2025 Jul 25. 25(1): 263

Combined bulk and single-cell transcriptomic analysis reveals cell-type-specific inflammatory crosstalk in pancreatic cancer.

Ahmad Golestanifar, Mana Zakeri, Sahar Gohari-Lasaki, Hengameh Khedri, Mohammadreza Saberiyan.

   OBJECTIVES: This study aims to elucidate the complex molecular and cellular landscape of pancreatic ductal adenocarcinoma (PDAC) by identifying key regulatory non-coding RNAs (ncRNAs), hub protein-coding genes, and Intercellular communication pathways that may serve as prognostic biomarkers and therapeutic targets.
BACKGROUND: Pancreatic cancer remains one of the deadliest malignancies worldwide, characterized by late diagnosis, limited treatment response, and poor prognosis. Among its histological subtypes, PDAC accounts for over 80% of cases and is defined by a highly fibrotic and immunosuppressive tumor microenvironment (TME).
METHODS: We performed a comprehensive bioinformatics analysis integrating multiple transcriptomic datasets from the NCBI Gene Expression Omnibus (GEO), including mRNA, miRNA, lncRNA, and circRNA profiles from PDAC and adjacent normal tissues. Differential expression analysis was conducted using GEO2R, followed by functional enrichment via DAVID. Hub genes were identified from protein-protein interaction (PPI) networks constructed using STRING and validated using GEPIA2. A competing endogenous RNA (ceRNA) network was developed to investigate regulatory ncRNA-mRNA axes. To refine these findings, single-cell RNA-seq (scRNA-seq) data were analyzed to resolve the cellular origin of hub genes and ncRNAs, and CellChat was employed to model intercellular communication within the TME.
RESULTS: We identified several dysregulated genes and ncRNAs implicated in key oncogenic pathways, including ECM remodeling, inflammation, and immune evasion. The ceRNA network highlighted functional interactions between circRNAs, lncRNAs, and miRNAs regulating key hub genes. Single-cell analysis revealed cell-type-specific expression of hub genes-e.g., FN1 and COL11A1 in fibroblasts, CXCL8 in macrophages, and ITGA3 in ductal cells-and uncovered a macrophage-endothelial CXCL8-ACKR1 signaling axis potentially driving tumor-associated angiogenesis. Moreover, correlations with immune cell infiltration and drug sensitivity further underscored the translational relevance of the identified molecular targets.
CONCLUSION: Our analysis combining bulk and single-cell transcriptomics provides a multi-scale view of PDAC pathogenesis. The findings highlight the interplay between ncRNAs, hub genes, and cellular crosstalk in shaping the tumor ecosystem and suggest novel targets for precision therapeutic intervention and biomarker development.

Keywords:  Bioinformatics analysis; CellChat; Non-coding RNA; Pancreatic Cancer; RNA-seq; Single-cell; circRNA-miRNA-mRNA; scRNA-seq

DOI:  https://doi.org/10.1007/s10238-025-01815-8
Clin Transl Med. 2025 Jul;15(7): e70404

PDK4 and nutrient responses explain muscle specific manifestation in mitochondrial disease.

Swagat Pradhan, Takayuki Mito, Nahid A Khan, Sofiia Olander, Aleksandra Zhaivoron, Thomas G McWilliams, Anu Suomalainen.

   BACKGROUND: Mitochondria elicit various metabolic stress responses, the roles of which in diseases are poorly understood. Here, we explore how different muscles of one individual-extraocular muscles (EOMs) and quadriceps femoris (QFs) muscles-respond to mitochondrial disease. The aim is to explain why EOMs atrophy early in the disease, unlike other muscles.
METHODS: We used a mouse model for mitochondrial myopathy ("deletor"), which manifests progressive respiratory chain deficiency and human disease hallmarks in itsmuscles. Analyses included histology, ultrastructure, bulk and single-nuclear RNA-sequencing, metabolomics, and mitochondrial turnover assessed through in vivo mitophagy using transgenic mito-QC marker mice crossed to deletors.
RESULTS: In mitochondrial muscle disease, large QFs upregulate glucose uptake that drives anabolic glycolytic one-carbon metabolism and mitochondrial integrated stress response. EOMs, however, react in an opposite manner, inhibiting glucose and pyruvate oxidation by activating PDK4, a pyruvate dehydrogenase kinase and inhibitor. Instead, EOMs upregulate acetyl-CoA synthesis and fatty-acid oxidation pathways, and accumulate lipids. In QFs, Pdk4 transcription is not induced.- Amino acid levels are increased in QFs but are low in EOMs suggesting their catabolic use for energy metabolism. Mitophagy is stalled in both muscle types, in the most affected fibers.
CONCLUSIONS: Our evidence indicates that different muscles respond differently to mitochondrial disease even in one individual. While large muscles switch to anabolic mode and glycolysis, EOMs actively inhibit glucose usage. They upregulate lipid oxidation pathway, a non-optimal fuel choice in mitochondrial myopathy, leading to lipid accumulation and possibly increased reliance on amino acid oxidation. We propose that these consequences of non-optimal nutrient responses lead to EOMatrophy and progressive external ophthalmoplegia in patients. Our evidence highlights the importance of PDK4 and aberrant nutrient signaling underlying muscle atrophies.

Keywords:  integrated stress response; mitochondrial disease; mitochondrial myopathy; nutrient signaling; progressive external ophthalmoplegia; pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.1002/ctm2.70404
Commun Biol. 2025 Jul 23. 8(1): 1093

Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans.

Xianghong Zhang, Jianguo Lin, Baobo Zou, Jack R Killinger, Andrew C Sayce, Thiagarajan Meyyappan, Zeyu Xiong, Melanie J Scott, Janet S Lee, Matthew R Rosengart.

Survivors of sepsis suffer from an elevated risk of premature death that is not explained by a higher burden of chronic diseases prior to the infection. Nearly 1 out of 4 survivors have persistent elevations of inflammation biomarkers, such as interleukin (IL) 6. These observations suggest that sepsis imparts durable changes to organismal biology. Eukaryotic life depends upon ATP and calcium (Ca2+). During sepsis, mitochondrial dysfunction, a failure of Ca2+ homeostasis, and sustained elevations in cytosolic [Ca2+] occur. These insults may serve as sufficient pressure to select for cells uniquely able to adapt. In this study of murine and human sepsis survivors, we observe that sepsis induces in lymphoid tissues a restructuring of the mitochondrial calcium uniporter (MCU) complex: the critical channel mediating the electrophoretic uptake of Ca2+ into the mitochondrion. We show these changes persist after clinical resolution of sepsis and lead to alterations in mitochondrial Ca2+ regulation, Ca2+ signaling, oxidative metabolism, and sensitivity to programmed cell death pathways. These biochemical changes manifest as fundamental alterations in phenotype: i.e., heightened systemic IL-6 concentration. Inhibiting lysosomal pathways partially restores the MCU complex stoichiometry, mitochondrial Ca2+ homeostasis, and lymphoid tissue phenotype to a sepsis naïve state.

DOI: https://doi.org/10.1038/s42003-025-08475-0