bims-musmir 2026-07-19 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–07–19
eight papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Sex-divergent skeletal muscle remodeling emerges early in cancer cachexia.
Differential impact of cancer- and chemotherapy-induced cachexia: a comparative analysis in a pre-clinical model of colorectal cancer by biological sex.
Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.
The Secretome of a Cachexia-Inducing Lung Tumor Impairs Mitochondrial Function and Skeletal Muscle Differentiation.
Brown fat-specific RNA labelling reveals a network of inter-organ communication by secreted microRNAs.
Ageing alters cysteine oxidation-regulated redox signalling in skeletal muscle: Integrative omics and AI-based structural predictions.
ROS-driven mitochondrial and mtDNA release as a novel pathway of metabolic injury in diabetes.
Silencing of BCAT1 induces ferroptosis and inhibits brain metastasis of non-small cell lung cancer via activating the cGAS-STING pathway.

Am J Physiol Cell Physiol. 2026 Jul 16.

Sex-divergent skeletal muscle remodeling emerges early in cancer cachexia.

Chris Karagiannis, Alastair A E Saunders, Rachel E Thomson, María Guillán-Fresco, Wayne X Du, Craig A Goodman, Paul Gregorevic.

  Cancer cachexia is characterised by progressive skeletal muscle wasting and dysfunction, yet the early events that precede overt muscle wasting remain poorly defined. Here, we utilised a time-coursed C26 carcinoma model in male and female mice to define the pre-cachectic transcriptomic, proteostatic, immune, and metabolic adaptations between sexes. Males progressed more rapidly to cachexia and exhibited earlier impairments in body composition and grip strength, with shifts in muscle fiber size distribution detectable prior to changes in muscle mass. Transcriptomic analysis of the tibialis anterior muscle identified >6,000 differentially expressed genes, with >60% showing sex-specific regulation at the pre-cachectic stage. Proteostasis pathways were transcriptionally altered in both sexes, however, global muscle protein synthesis was suppressed earlier in males, preceding both measurable muscle mass loss and robust induction of specific E3 ubiquitin ligases. Transcripts related to innate immunity were preferentially elevated in males and accompanied by increased infiltration of myeloid cells, while systemic immune profiles showed limited concordant changes. Females showed preferential enrichment of insulin resistance and metabolic remodeling pathways, accompanied by early impairment of insulin handling and reduced muscle glycogen content at severe cachexia. These results show that cachexia progression in this model is sexually dimorphic and skeletal muscle undergoes extensive remodeling before overt wasting. Males exhibit earlier functional decline and muscle immune remodeling, whereas females show earlier metabolic vulnerability with impaired insulin handling. These findings define sex-divergent pre-cachectic windows that may guide early biomarker discovery and therapeutic strategies aimed at preventing progression and improving quality of life in cancer patients.

Keywords:  Cancer-cachexia; flow-cytometry; insulin-resistance; protein-metabolism; transcriptomics

DOI:  https://doi.org/10.1152/ajpcell.00271.2026
Am J Physiol Endocrinol Metab. 2026 Jul 15.

Differential impact of cancer- and chemotherapy-induced cachexia: a comparative analysis in a pre-clinical model of colorectal cancer by biological sex.

Ana Regina Cabrera, Eleanor R Schrems, Ruqaiza Muhyudin, Francielly Morena, Stavroula Tsitkanou, Ronald G Jones, Kaitlyn Parker, Morghan Relich, Kevin A Murach, Timothy J Muldoon, Tyrone A Washington, Nicholas P Greene.

  Cancer cachexia is a wasting condition characterized by muscle loss and reduced quality of life in cancer patients. Although biological sex differences in the progression of cancer cachexia have been increasingly recognized, their role during chemotherapy-treated cancer cachexia remains largely unexplored. We evaluated such potential differences using male and female mice implanted subcutaneously with Colon-26 allografts. Our novel approach to disentangle the effects of chemotherapy consisted of administering two cycles of 75% of the maximum tolerated dose of 5-fluorouracil, cisplatin, or paclitaxel, in the presence and absence of cancer (n=6-11/condition). Muscles and organs were collected 25 days following tumor implant, and protein turnover markers, gene expression through RNA sequencing, and mitochondrial function were evaluated in gastrocnemius. A two-way factorial analysis was conducted to assess main effects and interactions across groups (p<0.05). We demonstrate chemotherapy exhibited preserved fat mass in males while maintained body weight in females. Chemotherapy elicited negative impacts on muscle in both sexes, even in a reduced or absent tumor burden. In males, protein synthesis was lower in the presence of cancer and chemotherapy without corresponding differences in atrogenes. Cluster analysis revealed largest differences in muscle transcriptome between cancer control and C26-paclitaxel in male mice, highlighting altered regulation of ubiquitin-mediated proteolysis. These findings point to divergent mechanisms during protein processing in endoplasmic reticulum regulation in muscle atrophy associated with cancer in the presence of chemotherapy. Our results highlight distinct mechanisms underlying cancer-cachexia alone versus the addition of chemotherapy and further indicate responses to chemotherapy differ between biological sexes.

Keywords:  5-fluorouracil; Atrophy; Cisplatin; Muscle loss; Paclitaxel; Protein Processing; Skeletal muscle

DOI:  https://doi.org/10.1152/ajpendo.00131.2026
Mol Metab. 2026 Jul 17. pii: S2212-8778(26)00106-7. [Epub ahead of print] 102422

Pre-clinical cancer cachexia causes glucose hypermetabolism prior to overt weight loss.

Emma Frank, Kaspar W Persson, Pauline Morigny, Zakarias Kefil Jensen Ogueboule, Tang Cam Phung Pham, Jonas R Knudsen, Maria Rohm, Lykke Sylow, Steffen H Raun.

   PURPOSE: Cancer cachexia is a life-threatening complication of advanced malignancies, driven by profound systemic metabolic reprogramming and anorexia. Insulin action is markedly impaired in patients with cancer and may contribute directly to cachexia pathogenesis. However, the interplay between weight loss, food intake, and cancer-associated metabolic rewiring in cachexia remains poorly defined. Clarifying this relationship is essential for identifying the fundamental drivers of cachexia and for developing effective therapeutic strategies.
METHODS: We assessed metabolic rewiring by temporal evaluation of glucose tolerance and isotopic tracers to determine muscle insulin-stimulated glucose uptake in male cachectic and non-cachectic C26- and KPC-tumor-bearing, as well as healthy mice undergoing food restriction.
RESULTS: Cachectic C26- and KPC-tumor mice showed increased glucose tolerance compared to non-tumor-bearing control mice, and non-cachectic tumor-bearing mice. Increased glucose tolerance appeared prior to overt muscle loss, independent of tumor size and changes in food intake. Ex vivo insulin-stimulated glucose uptake was elevated in soleus (+78%) and extensor digitorum longus (+35%) muscle from cachectic C26-cancer mice with anorexia compared to weight stable C26-cancer mice and control mice. This increase was associated with enhanced AKT signaling. Food restriction in healthy mice increased glucose tolerance, insulin-stimulated glucose uptake ex vivo, and AKT signaling.
CONCLUSIONS: Our findings suggest that glucose hypermetabolism appears prior to overt weight loss in pre-clinical cachexia, whereas late-stage cachexia with anorexia increased skeletal muscle insulin responsiveness. This highlights AKT signaling as a key node connecting nutrient status with muscle metabolism in cancer cachexia.

Keywords:  Cancer cachexia; food restriction; glucose metabolism; insulin sensitivity; muscle

DOI:  https://doi.org/10.1016/j.molmet.2026.102422
Cancers (Basel). 2026 Jun 30. pii: 2130. [Epub ahead of print]18(13):

The Secretome of a Cachexia-Inducing Lung Tumor Impairs Mitochondrial Function and Skeletal Muscle Differentiation.

Nikki Wanders, Marvin Martens, Marco Kelders, Sven Manse, Sandra van Krimpen, Claire Groenen, Chrysi Kapsali, Paula Bilbao Fraile, Konstantina Bermperi, Niels Boumans, Youssra Ahidar, Ludwig Dubois, Hubert Smeets, Wouter van de Worp, Ramon Langen.

  Background: Cancer-associated cachexia (CAC) can affect up to 80% of patients with late-stage cancer and is characterized by depletion of skeletal muscle mass with or without loss of fat tissue. No effective treatments are currently available, and reversing CAC requires understanding the intracellular processes of muscle atrophy and its cancer-related extracellular triggers. In this study, we aimed to disentangle tumor- and host-driven mechanisms in CAC muscle wasting. Methods: In skeletal muscle tissue obtained from control non-tumor-bearing mice and cachectic mice resulting from orthotopically implanted 344P lung adenocarcinoma cells, transcriptomic analyses were performed to identify muscle wasting-associated processes. To explore whether these reflected direct tumor-induced effects, 344P tumor-conditioned medium (tCM) was applied to in vitro cultured C2C12 skeletal muscle cells to investigate the impact on muscle proteolysis, myogenesis and mitochondrial function. Results: RNAseq data revealed increased proteolysis along with decreased myogenesis-related processes, and prominent downregulation of genes encoding mitochondrial OXPHOS complexes, in cachectic mouse muscle. Exposure of cultured skeletal muscle cells to tCM reduced mitochondrial respiration and induced changes in mitochondrial mass and mitochondrial DNA copy number. tCM did not induce myotube atrophy, or activation of proteolysis-related signaling, in fully differentiated myotubes. In contrast, tCM reversibly inhibited myoblast-myotube fusion, and reduced myogenic and muscle-specific gene expression in differentiating myoblasts. Application of CCCP to simulate muscle mitochondrial dysfunction reproduced the myogenesis-impairing phenotype caused by tCM. Conclusions: Our results show that factors present in the cachexia-inducing lung tumor secretome directly impair myogenesis and muscle mitochondrial function, whereas activation of muscle catabolic processes requires host-dependent mechanisms.

Keywords:  C2C12; cachexia; lung adenocarcinoma; muscle wasting

DOI:  https://doi.org/10.3390/cancers18132130
Nat Metab. 2026 Jul 16.

Brown fat-specific RNA labelling reveals a network of inter-organ communication by secreted microRNAs.

Marsel Lino, Gabriel Palermo-Ruiz, Vissarion Efthymiou, Alice Rodrigues, Shraddha Bhonsle, Allah Nawaz, Anindya Ghosh, Bruna Brasil Brandão, Yoshiyuki Watanabe, Rafael Barrera Salgueiro, Yingying Yu, C Ronald Kahn.

Extracellular microRNAs (miRNAs) are emerging as key regulators of organismal homeostasis. Here, using tissue-specific RNA labelling based on uracil phosphoribosyltransferase-mediated incorporation of 4-thiouracil in male mice, we develop a roadmap of miRNA transfer from brown adipose tissue (BAT) to other tissues, where they can act to regulate energy metabolism. We show that BAT secretes miRNAs in both small extracellular vesicles and is associated with plasma proteins, and that miRNAs in both compartments exhibit tissue-selective uptake in the liver, muscle and hypothalamus. Disruption of Dicer in BAT leads to a significant depletion of multiple miRNAs in both BAT and distal tissues, including 80-90% decreases in the most abundant miRNAs in muscle. Target analyses, in vitro modelling and PAR-CLIP analysis in muscle in vivo confirm that these BAT-secreted miRNAs directly interact with target mRNAs and alter mitochondrial function in recipient tissues. These findings provide a framework for understanding the role of BAT-secreted miRNAs in inter-organ communication.

DOI: https://doi.org/10.1038/s42255-026-01558-0
Exp Physiol. 2026 Jul 11.

Ageing alters cysteine oxidation-regulated redox signalling in skeletal muscle: Integrative omics and AI-based structural predictions.

Ufuk Ersoy, Malcolm J Jackson.

  Ageing is associated with loss of skeletal muscle mass and strength (sarcopenia) and disrupted redox homeostasis. Redox signalling is essential for muscle adaptation, yet the mechanisms by which ageing disrupts cysteine-based regulation are poorly defined. The drivers of site-specific reactivity and signalling specificity in aged muscle remain unknown. Here, we interrogated the OxiMouse dataset to map age-related cysteine oxidation in skeletal muscle and, using AI, simulate oxidative modifications at key cysteine residues to predict structural and functional consequences for specific proteins. Ageing was found to remodel the redox landscape through selective oxidation of discrete cysteine residues, in a site-specific manner, even within the same protein. These findings support that ageing drives pathway-targeted modulation of protein function rather than a uniform, global oxidative shift. Moreover, age-related cysteine oxidation is not randomly distributed but appears to target interconnected protein networks involved in mitochondrial metabolic pathways, muscle function and proteostasis, indicating a coordinated remodelling in redox signalling as a hallmark of skeletal muscle ageing. To connect proteomic signatures to mechanisms, AlphaFold3 was used to simulate progressive cysteine oxidation and predict structural outcomes. Protein docking simulations were then performed using HADDOCK. This approach was applied to prioritise functionally important cysteines identified in the dataset. These results suggest that skeletal muscle ageing drives selective rewiring of physiologically relevant cysteine-based redox signalling networks. By integrating redox proteomics with AI-based structural simulation, this study provides a framework to prioritise key oxidation-sensitive cysteines, including within the 26S proteasome, as potential mechanistic nodes and intervention targets for sarcopenia.

Keywords:  ageing; alphafold3; cysteine; proteomics; reactive oxygen species; skeletal muscle

DOI:  https://doi.org/10.1113/EP093750
J Mol Endocrinol. 2026 Jul 15. pii: JME-25-0203. [Epub ahead of print]

ROS-driven mitochondrial and mtDNA release as a novel pathway of metabolic injury in diabetes.

Dandan Chen, Yuxin Jia, Xiaohong Duan, Jianhua Huang, Xiaohong Deng.

  Mitochondrial dysfunction driven by chronic hyperglycemia is a hallmark of diabetes, yet how this metabolic stress communicates pathological signals beyond individual cells remains poorly understood. In this study, we identified a novel mechanism linking chronic hyperglycemia to systemic metabolic impairment through ROS-mediated extracellular release of structurally intact mitochondria and mitochondrial DNA (mtDNA). In HepG2 cells exposed to high glucose (HG), extracellular release of structurally intact mitochondria was visualized by co-staining of mitochondria and the plasma membrane, together with electron microscopy. Mitochondria-enriched fractions isolated from culture supernatants were further quantified using flow cytometry and qPCR. Cell-free mtDNA (cf-mtDNA) was visualized with co-staining of mitochondria and double- stranded DNA, isolated through differential centrifugation and ultrafiltration, and quantified by qPCR. We demonstrate that HG stimulates the release of exosome-enclosed mtDNA as well as fragmented cf-mtDNA. Concurrently, HG induces mitochondrial dysfunction and markedly increases mitochondrial ROS (mtROS). Treatment with MitoTEMPO, a mitochondria-targeted ROS scavenger, significantly reduced HG-induced extracellular release of mitochondria and mtDNA, supporting the ROS dependence of this process. In diabetic mice, we detected elevated circulating mtDNA copy number and pronounced mitochondrial dysfunction in liver and muscle, including reduced ATP production, mitochondrial swelling, cristae disruption, and elevated MDA levels. Resting metabolic rate was markedly decreased, indicating impaired systemic respiratory metabolism. Serum analyses revealed increased 8-OHdG, pyruvic acid, GDF-15, and FGF-21, along with reduced FT3, reflecting severe oxidative stress and mtDNA damage. These findings uncover a novel mechanism in which hyperglycemia-induced ROS drive mitochondrial extrusion, potentially linking metabolic stress to systemic metabolic deterioration.

Keywords:  Diabetes mellitus; ROS; mitochondrial release; resting metabolic rate

DOI:  https://doi.org/10.1530/JME-25-0203
J Thorac Dis. 2026 Jun 30. 18(6): 578

Silencing of BCAT1 induces ferroptosis and inhibits brain metastasis of non-small cell lung cancer via activating the cGAS-STING pathway.

Fan Yang, Yuying Li, Huijiao Zhou, Xin Bi, Dongjie Wang.

   Background: Brain metastasis (BM) in non-small cell lung cancer (NSCLC) is associated with the reprogramming of branched-chain amino acid (BCAA) metabolism. This investigation sought to comprehend the function and molecular process of BCAT1 during the BM associated with NSCLC.
Methods: BCAT1 expression was assessed in NSCLC brain metastases (NSCLC-BM) tissues and NSCLC cell lines using quantitative real-time PCR and western blotting. In vitro, malignant cell processes, BCAA metabolism, and ferroptosis were evaluated. A mouse model of NSCLC-BM was created to evaluate the function of BCAT1 and the cGAS-STRING pathway in vivo. Western blotting was performed to determine whether BCAT1 mediated the cGAS-STING pathway.
Results: BCAT1 expression was elevated in NSCLC-BM tissues and cells. Knocking down BCAT1 inhibited cell viability, migration, invasion, epithelial-mesenchymal transition (EMT), and stemness, disrupted BCAA metabolic reprogramming, and promoted ferroptosis in vitro. Moreover, BCAT1 silencing suppressed tumor BM in vivo. The cGAS-STING pathway was activated after BCAT1 knockdown via triggering mitochondrial DNA leakage, and inhibition of this pathway reversed the cellular behaviors in vitro and BM in vivo induced by BCAT1 silencing.
Conclusions: In conclusion, BCAT1 promotes NSCLC-BM by modulating BCAA metabolic reprogramming through suppressing the cGAS-STING pathway, highlighting the potential of BCAT1 to be targeted in therapy.

Keywords:  BCAT1; Non-small cell lung cancer (NSCLC); brain metastasis (BM); branched-chain amino acid metabolism (BCAA metabolism); the cGAS-STING pathway

DOI:  https://doi.org/10.21037/jtd-2026-1-0269