bims-musmir 2026-07-26 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–07–26
twenty papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Multi-organ transcriptome profiling in an isogenic cachexia-inducing xenograft model to dissect host responses across heart, liver, kidney, and muscle.
Site-targeted proximal complement C3 inhibition, but not C5 blockade, attenuates neurodegeneration in a mouse model of amyotrophic lateral sclerosis: Implications for failed clinical trials.
Identifying potential biomarkers for mild COVID-19 in saliva by miRNA profiling using NGS and ddPCR.
The dual face of miR-146a in ALS.
Muscle Mitochondrial Oxidative Capacity and Cognitive Decline Over up to a Decade: Sex Differences.
The local-systemic axis of the skeletal muscle secretome.
FUS controls muscle differentiation through phase separation-mediated recruitment of the transcription factors MEF2 and ETV5.
Effects of aging in combination with high-fat or ketogenic diet on skeletal muscle hypertrophy after functional overloading in C57BL/6J mice.
Selective Small-Molecule AdipoR1 Agonist 3-Hydroxy Pterocarpan Salt (CDRI-1709S) Ameliorates Skeletal Muscle Atrophy.
Mitochondrial RNA modifications in gene expression and cancer biology.
Diet-induced obesity fails to prime tumour-associated neuroinflammation in mice with Lewis Lung Carcinoma.
ER stress-dependent Ddit4/REDD1 induction contributes to translational suppression during cisplatin-induced skeletal muscle atrophy.
Toward a comprehensive modification landscape of yeast mitochondrial tRNAs using Nanopore direct RNA sequencing and dihydrouridine sequencing.
Quercetin attenuates cisplatin-induced muscle atrophy via Hippo/YAP1 signaling pathway.
TTYH3 regulates a lysosomal chloride conductance and controls lysosomal fusion, autophagy and senescence.
The Injection of miR-1/133 Antagonist Notably Accelerated the Healing Process of Exercise-Induced Skeletal Muscle Injury.
Rethinking frailty as a disorder of mitochondrial adaptability, from energetic congestion to systemic vulnerability.
Exploring the Relationship Between Skeletal Muscle Mass and Muscle Strength in the Limbs of Elite Soccer Players.
Nutritional support for cancer cachexia: A systematic review and meta-analysis of randomized controlled trials.
FMRP regulates neuronal RNA granules containing stalled ribosomes, not where ribosomes stall.

Hum Cell. 2026 Jul 19. pii: 112. [Epub ahead of print]39(8):

Multi-organ transcriptome profiling in an isogenic cachexia-inducing xenograft model to dissect host responses across heart, liver, kidney, and muscle.

Julia Osaki, Yomogi Shiota, Ikumi Fujita, Kazuyoshi Yanagihara, Tadashi Kondo.

  Cancer cachexia is a debilitating systemic syndrome that affects a substantial proportion of patients with advanced malignancy and is associated with impaired treatment tolerance, reduced quality of life, and increased mortality. While skeletal muscle wasting is a defining clinical feature, cachexia involves coordinated dysfunction across multiple organs, yet it remains unclear whether cachexia imposes a unified, body-wide transcriptional program or primarily induces organ-specific responses. Here, we leveraged an isogenic xenograft model derived from human duodenal neuroendocrine carcinoma in which the cachexia-inducing subline AkuNEC was established through in vivo serial passaging from the parental, largely non-cachexia-inducing line TCC-NECT-2. We performed bulk RNA sequencing of skeletal muscle, liver, kidney, and heart from cachectic AkuNEC-bearing mice, non-cachectic TCC-NECT-2-bearing mice, and uninoculated controls. Differential expression analyses identified organ-dependent sets of transcripts associated with cachexia. However, unsupervised analyses of global expression patterns consistently showed that tissue identity dominated transcriptome structure and samples did not segregate by cachexia status. In addition, comparisons of tumor-bearing vs uninoculated controls revealed broadly similar transcriptional shifts for AkuNEC and TCC-NECT-2 within each organ. Together, these data indicate that cachexia-associated transcriptional changes are present but remain modest relative to dominant tissue-specific programs at the whole-transcriptome level. The AkuNEC/TCC-NECT-2 system provides a controlled platform for future studies incorporating cell-type-resolved, spatial, and multi-omic approaches to delineate the mechanisms linking tumor evolution to multi-organ remodeling in cancer cachexia.

Keywords:  AkuNEC; Cancer cachexia; Duodenal neuroendocrine carcinoma; Heart; Kidney; Liver; Multi-organ dysfunction; RNA-seq; Skeletal muscle; TCC–NECT-2; Transcriptomics; Xenograft

DOI:  https://doi.org/10.1007/s13577-026-01412-1
Neurotherapeutics. 2026 Jul 23. pii: S1878-7479(26)00139-X. [Epub ahead of print]23(5): e00969

Site-targeted proximal complement C3 inhibition, but not C5 blockade, attenuates neurodegeneration in a mouse model of amyotrophic lateral sclerosis: Implications for failed clinical trials.

Moumita Majumder, Davis M Borucki, Nityananda Chowdhury, Khalil Mallah, Stephen Tomlinson.

  Complement activation contributes to amyotrophic lateral sclerosis (ALS) neuropathology, but whether motor neuron degeneration is driven by proximal or terminal activation products remains unresolved. Failed trials of C5 inhibition - ravulizumab (CHAMPION-ALS) and zilucoplan (ATHLEET/HEALEY ALS Trial), and of systemic C3 inhibition (pegcetacoplan, MERIDIAN) underscore this mechanistic gap. We compared two pharmacologically distinct inhibitors in hSOD1G93A mice. CR2Crry blocks complement at C3 and localizes to sites of active deposition. BB5.1, functionally equivalent to ravulizumab, selectively blocks C5a generation and membrane attack complex (MAC) assembly. Treatment began at symptom onset and continued to humane endpoint. Both agents achieved robust target engagement across spinal cord, sciatic nerve, and neuromuscular junction (NMJ). Only CR2Crry extended survival, preserved motor function, and attenuated weight loss. CR2Crry reduced microglial activation and C3 opsonization in the ventral horn, diminished macrophage infiltration, preserved sciatic nerve axonal integrity, and maintained NMJ innervation. BB5.1 failed to modify any functional or neurodegenerative pathology despite confirmed MAC suppression. Proximal C3 activation products, not C5a or MAC, are the dominant drivers of complement-mediated neurodegeneration in the hSOD1G93A model of ALS. Site-targeted C3 inhibition may address the mechanistic limitation underlying recent clinical trial failures and represents a translationally justified therapeutic strategy.

Keywords:  ALS; C3; Neuroinflammation; Site-targeted complement inhibition; hSOD1(G93A)

DOI:  https://doi.org/10.1016/j.neurot.2026.e00969
Sci Rep. 2026 Jul 20.

Identifying potential biomarkers for mild COVID-19 in saliva by miRNA profiling using NGS and ddPCR.

Malena Gajate-Arenas, Candela Sirvent-Blanco, Omar García-Pérez, Angélica Domínguez-De-Barros, Alma García-Ramos, Jose E Piñero, Jacob Lorenzo-Morales, Elizabeth Córdoba-Lanus.

  MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression by targeting messenger RNA (mRNA). Due to this regulatory function, viruses often modulate host miRNA expression to facilitate their own replication. Conversely, host cells regulate miRNA expression to activate the immune system response. As a result, miRNAs represent promising biomarkers for infectious diseases, including viral respiratory infections, in which the upper airways serve as the primary entry point. Therefore, saliva provides valuable insights into the patient's condition. Advancing techniques and methodologies for saliva analysis is essential. In the present study, saliva screening for miRNA expression was performed using next generation sequencing (NGS). We then validated our findings with digital droplet PCR (ddPCR) and quantitative PCR (qPCR). Additionally, we conducted in-silico analyses to identify the target genes and biological pathways associated with the dysregulated miRNAs and their roles in SARS-CoV-2 infection. The screening step pointed to miR-590-3p and miR-374a-5p being downregulated in COVID-19. Subsequent validation using qPCR and droplet digital PCR (ddPCR) confirmed the downregulation of these miRNAs in COVID-19 cases. Under the experimental conditions evaluated in this study, ddPCR showed improved analytical sensitivity and quantitative agreement compared with RT-qPCR for detecting low-abundance salivary miRNAs, thereby strengthening the robustness of our findings. Under the experimental conditions evaluated in this study, ddPCR showed improved analytical sensitivity and quantitative agreement compared with RT-qPCR for the detection of low-abundance salivary miRNAs. The functional analyses revealed that both miRNAs are involved in viral processes and apoptosis regulation. Moreover, the conservation of miR-374a-5p and miR-590-3p across different groups of mammals highlights the relevance of their regulatory roles. Taken together, these results suggest that miR-374a-5p and miR-590-3p may serve as suitable biomarkers for SARS-CoV-2 infection.

Keywords:  COVID-19; NGS; Saliva; ddPCR; microRNAs

DOI:  https://doi.org/10.1038/s41598-026-62840-5
Proc Natl Acad Sci U S A. 2026 Jul 28. 123(30): e2617170123

The dual face of miR-146a in ALS.

Guy Haim, Eran Hornstein.

DOI: https://doi.org/10.1073/pnas.2617170123
Aging Cell. 2026 Aug;25(8): e70637

Muscle Mitochondrial Oxidative Capacity and Cognitive Decline Over up to a Decade: Sex Differences.

Qu Tian, Anjay Ambegaonkar, Luigi Ferrucci.

Higher skeletal muscle oxidative capacity is associated with higher cognitive function and preserved brain structure. The relationship between mitochondria and brain health suggests sex differences, but whether the relationship with cognition shows sex differences and underlying mechanisms is unknown. We analyzed the relationships between mitochondrial oxidative capacity and up to 12-year prospective cognitive data in 506 older participants (mean age = 74.4 years, 58% Women) and examined sex differences, using linear mixed-effects models adjusted for demographics. Cognitive composite scores were computed using multiple cognitive measures. Muscle oxidative capacity was assessed as the post-exercise recovery rate of phosphocreatine (kPCr) via phosphorus-31 MR spectroscopy. We tested mediation effects of blood-based clinical markers. Cross-sectionally, higher kPCr was associated with higher cognitive scores (p < 0.001 overall, p = 0.001 men, p = 0.029 women), and there was no significant kPCr-by-sex interaction (p = 0.308). Longitudinally, there was a significant kPCr-by-sex interaction (p = 0.042). The association of higher kPCr with slower cognitive decline was prominent in men (p = 0.077), particularly executive function (p = 0.010) and processing speed (p = 0.049). In men, fasting glucose and hemoglobin A1C mediated both cross-sectional and longitudinal associations between kPCr and cognition (all p < 0.05, 23.1% by glucose). Total protein and globulin also mediated the cross-sectional association in men to a lesser extent (9.5%-9.9%). In women, ESR, hemoglobin, and hematocrit mediated the cross-sectional association (all p < 0.05, 22.7% by hematocrit). Muscle mitochondria are linked to cognition and predict cognitive decline primarily in men. Underlying mechanisms appear to differ by sex, likely through a metabolic-drive pathway in men and a hematologic-inflammatory pathway in women. Omics studies are warranted to elucidate the sex-specific biological processes.

DOI: https://doi.org/10.1111/acel.70637
Trends Endocrinol Metab. 2026 Jul 24. pii: S1043-2760(26)00172-4. [Epub ahead of print]

The local-systemic axis of the skeletal muscle secretome.

Sean Y Ng, Christoph Handschin.

  Exercise stimulates the release of bioactive factors, termed exerkines, that contribute to local and systemic adaptation. Circulating exerkines are often interpreted as direct readouts of muscle secretion, overlooking regulatory processes within tissues that shape their production, transformation, and release. Using skeletal muscle and endurance exercise as a model system, we define a local-systemic secretome axis shaped by spatial organization, stimulus-specific programs, temporal dynamics, extracellular processing, and paracrine circuitry. By integrating evidence from recent transcriptomics, proteomics, interstitial fluid, and extracellular vesicle studies, we outline how these processes govern signal propagation from muscle to circulation and inform the interpretation of circulating exerkines as biomarkers and therapeutic targets.

Keywords:  exercise adaptation; exerkine; paracrine signaling; secretome; skeletal muscle

DOI:  https://doi.org/10.1016/j.tem.2026.07.001
EMBO J. 2026 Jul 22.

FUS controls muscle differentiation through phase separation-mediated recruitment of the transcription factors MEF2 and ETV5.

Gina Picchiarelli, Anne Wienand, Salim Megat, Saskia Hutten, Amr Aly, Marije Been, Isabelle Weber, Angela Bonanno, Nibha Mishra, Erin Sternburg, Pierre Cauchy, Stéphane Dieterle, Marica Catinozzi, Javier Lobo-Mancheno, Hannah Walgrave, Valérie Demais, Pierre Hener, Pascal Kessler, Laura Tzeplaeff, Annemarie Huebers, Dagmar Zeuschner, Angela Rosenbohm, Albert C Ludolph, Anne-Laurence Boutillier, Tobias Boeckers, Dorothee Dormann, Maria Demestre, Chantal Sellier, Clotilde Lagier-Tourenne, Erik Storkebaum, Luc Dupuis.

FUS is an RNA-binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show in this work that a heterozygous knock-in mutation in the mouse Fus gene leads to cell-autonomous ultrastructural defects in skeletal muscle, with disruption of sarcomeres and mitochondria. Studies in mouse and Drosophila models demonstrate an evolutionarily conserved cell-autonomous function of FUS in muscle development. Mechanistically, FUS is required for the transcription of MEF2 target genes, binds to the promoter of genes bound by ETS transcription factors, in particular ETV5, and co-activates the transcription of MEF2-dependent genes with ETV5. FUS phase-separates with ETV5 and MEF2A, and stimulation of MEF2-dependent transcription by FUS is dependent upon its phase separation properties. Finally, Etv5 haploinsufficiency exacerbates muscle weakness and atrophy in Fus knock-in mice. Our findings establish a key role for FUS in skeletal muscle differentiation through its phase separation-dependent recruitment of ETV5 and MEF2, defining a novel pathway compromised in FUS-ALS.

DOI: https://doi.org/10.1038/s44318-026-00874-1
Growth Factors. 2026 Jul 19. 1-13

Effects of aging in combination with high-fat or ketogenic diet on skeletal muscle hypertrophy after functional overloading in C57BL/6J mice.

Mantas Dirmontas, Petras Minderis, Aivaras Ratkevicius.

  We investigated how aging interacts with high-fat (HFD) and ketogenic (KD) diets to influence functional overload (FO)-induced muscle hypertrophy in C57BL/6J mice. Male mice aged 3, 16, and 24 months were fed regular chow (RD), HFD, or KD for 12 weeks, with FO of the plantaris muscle induced by denervation of the soleus and gastrocnemius during the final 6 weeks (n = 8-10 per group). Muscle hypertrophy was unaffected by diet (p = 0.897) but declined with age (p < 0.001), with a marked reduction already in mature mice. Plasma IGF-1 was higher in adult than mature (p < 0.05) and old (p < 0.001) mice and correlated positively with hypertrophy (r = 0.29, p = 0.01). The weak correlation of hypertrophy with plasma IGF-I levels suggests that IGF-I is only one among many factors playing a role in muscle hypertrophy.

Keywords:  High-fat diet; IGF-1; aging; ketogenic diet; muscle hypertrophy

DOI:  https://doi.org/10.1080/08977194.2026.2704554
J Cachexia Sarcopenia Muscle. 2026 Aug;17(4): e70328

Selective Small-Molecule AdipoR1 Agonist 3-Hydroxy Pterocarpan Salt (CDRI-1709S) Ameliorates Skeletal Muscle Atrophy.

Md Rameez Moin, Shyamal Pal, Shubhrajyoti Das, Pallavi Awasthi, Anushka Talukdar, Akhilesh Kumar, Shruti Suhas Varode, Nikhil Nikolas, Shamima Khatoon, Madhav Nilkanth Mugale, Rajdeep Guha, Sabyasachi Sanyal, Atul Goel.

   BACKGROUND: Skeletal muscle atrophy is a frequent comorbidity of metabolic disorders and chronic diseases, and despite its high prevalence, no pharmacological therapy is available, representing a major unmet clinical need. Adiponectin and its receptors are key regulators of skeletal muscle metabolism, mitochondrial function and myogenesis, yet clinical translation has been hindered by the lack of receptor-selective agonists with favourable pharmacological and safety profiles. Here, we report the identification and characterization of CDRI-1709S, the first small-molecule AdipoR1-selective agonist and evaluate its myogenic and anti-atrophy efficacy.
METHODS: A PGC-1α luciferase reporter-based screen in AdipoR1/AdipoR2-transfected, AdipoR-low HEK293T cells identified CDRI-1709S as an AdipoR1 agonist. Adiponectin-associated signalling events were evaluated by immunoblotting in AdipoR1/2-overexpressing HEK293T cells and AdipoR-abundant C2C12 myotubes, with receptor specificity confirmed using RNA interference. Myogenic potential was assessed by morphometric analysis and immune detection of myogenic factors. Fibre-type composition and metabolic capacity were evaluated using immunoblotting and extracellular flux analysis. Anti-atrophy effects were examined in vitro using various assault-induced models of myotube atrophy, and in vivo using rat models of dexamethasone (Dex) and sciatic nerve denervation-induced muscle atrophy.
RESULTS: CDRI-1709S selectively activated AdipoR1 with high potency (EC50: 414.7pM) and, at a pharmacologically relevant concentration (100 nM), induced rapid adiponectin-associated signalling, including phosphorylation of AMPK, AKT and p38-MAPK, along with upregulation of its downstream skeletal muscle metabolic targets PGC-1α, GLUT4 and UCP3 in an AdipoR1-dependent manner (p < 0.05). CDRI-1709S promoted C2C12 myoblast differentiation into mature myotubes, accompanied by increased expression of MyoD and myogenin (p < 0.05). Treated myotubes were protected against cytokine-, Dex- and nutrient-deprivation-induced atrophy through suppression of atrogenes Atrogin-1 and MuRF-1 (p < 0.01), restoration of myogenic markers (p < 0.05) and prevention of Dex-induced fibre-type switching toward glycolytic MyHC-IIB, with concomitant induction of slow (MyHC-I) and fast (MyHC-IIA) oxidative fibres (p < 0.05). CDRI-1709S also reversed Dex-mediated impairments in oxidative and glycolytic capacity (p < 0.05). Oral administration of CDRI-1709S (10 mg/kg/day) in Dex- and denervation-induced rat models restored atrogene expression, myogenic markers, local adiponectin signalling and myofibrillar architecture to normalcy (p < 0.05 to p < 0.0001). CDRI-1709S prevented Dex-induced enrichment of glycolytic fibres and preserved oxidative fibre composition (p < 0.05). The structural/molecular improvements translated into significant functional enhancements, including toe-spread reflex in denervated limbs (p < 0.05) and increased grip strength (p < 0.0001) plus prolonged wire-hang duration (p < 0.01) in Dex-treated animals.
CONCLUSION: CDRI-1709S is the first AdipoR1-selective small-molecule agonist that induced myogenesis and robustly ameliorated skeletal muscle atrophy, establishing the proof-of-concept for AdipoR1-targeting as a promising therapeutic strategy for sarcopenia and skeletal muscle atrophy.

Keywords:  AdipoR1 agonist; adiponectin; muscle fibre‐type; muscle function improvement; skeletal muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.70328
MedScience. 2026 Jul 24.

Mitochondrial RNA modifications in gene expression and cancer biology.

Haixia Wang, Lili Ren, Dongling Zou, Rui Su.

  RNA modifications are essential in regulating gene expression at the post-transcriptional level. Recent studies, including our own, have highlighted that RNA modifications, such as N6-methyladenosine (m6A) and methyl-5-cytosine (m5C), play a crucial role in tumorigenesis, metabolism, and anti-tumor immunity. Targeting RNA modification machinery may represent a promising therapeutic strategy in cancer. Intriguingly, emerging evidence reveals numerous modifications in mitochondrial RNA (mt-RNA), expanding the concept of epitranscriptomics to mitochondria. The mammalian mitochondrion possesses its own genome, which encodes 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 13 proteins necessary for energy production via oxidative phosphorylation (OxPhos). The mitochondrial transcriptome is produced from large polycistronic transcripts, implying that mitochondrial gene expression is predominantly regulated post-transcriptionally. In this review, we summarize all currently known mt-RNA modifications, their potential regulatory machinery, as well as their biological functions in tumorigenesis and metabolism. Additionally, given that this field is still in its infancy, we discuss several critical knowledge gaps and propose future research directions to clarify the mechanistic and clinical significance in the study of mt-RNA modifications.

Keywords:  RNA modifications; cancer; epitranscriptomics; metabolism; metastasis; mitochondria; tumor immunity

DOI:  https://doi.org/10.1007/s11684-026-1233-z
Neuroscience. 2026 Jul 24. pii: S0306-4522(26)00482-3. [Epub ahead of print]

Diet-induced obesity fails to prime tumour-associated neuroinflammation in mice with Lewis Lung Carcinoma.

Caroline G Fowler, Rebecca Rodriguez, Anna G Beaudry, Laura E Kusumo, Avery E Gillett, Michael P Wiggs, Michelle L Law, Elisabeth G Vichaya.

  As obesity rates rise throughout the world and, given that obesity increases cancer risk for many forms of cancer, we can expect the rates of comorbid obesity and cancer to also rise. While obesity increases cancer-related symptoms including fatigue, depression, and neuropathy, the mechanisms underlying this exacerbation are understudied. As cancer and obesity have both been associated with alterations in neuroinflammatory processes, we used a murine model to investigate the interaction between cancer and obesity-associated neuroinflammation. We hypothesized that diet-induced obesity would result in neuroinflammatory priming and exacerbate tumour-associated neuroinflammation. Across 3 experiments, we evaluated the effect of diet in both male and female C57BL6J mice and tested two different diet durations: (1) 9 weeks of 45% High-Fat Diet (HFD) in female mice, (2) 9 weeks of 45% HFD in male mice, and (3) 24 weeks of 45% HFD with 10% fructose water in male mice. Mice on HFD and Standard Diet (SD) were randomized to receive either an injection of Lewis Lung Carcinoma (LLC) cells or PBS vehicle subcutaneously into the flank. After tumors were allowed to grow for approximately 3 weeks, tissue was collected and proinflammatory cytokine expression was evaluated in the hippocampus and hypothalamus. Overall, our results indicate that while long-term HFD consumption led to poorer health outcomes (as measured by faster tumor growth, enhanced weight loss, and greater spleen weights), it failed to prime the neuroinflammatory response to tumors.

Keywords:  Cancer; Cytokines; High fat diet; Interleukin-1beta; Priming

DOI:  https://doi.org/10.1016/j.neuroscience.2026.07.038
Chem Biol Interact. 2026 Jul 18. pii: S0009-2797(26)00368-6. [Epub ahead of print]437 112260

ER stress-dependent Ddit4/REDD1 induction contributes to translational suppression during cisplatin-induced skeletal muscle atrophy.

Hayato Nanri, Hiroyasu Sakai, Kaisei Umeyama, Takayuki Ogiwara, Shinki Soga, Yuya Chigusa, Shiori Yonamine, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Kumiko Ogawa.

  Cisplatin is a widely used chemotherapeutic agent whose clinical utility is limited by various adverse effects. Although skeletal muscle loss during chemotherapy is often attributed to cachexia or generalized wasting, accumulating evidence indicates that cisplatin directly induces skeletal muscle atrophy. However, the underlying cellular stress responses and signaling pathways remain unclear. In this study, we investigated the involvement of endoplasmic reticulum (ER) stress and translational regulation in cisplatin-induced skeletal muscle atrophy, focusing on DNA damage-inducible transcript 4/Regulated in development and DNA damage response-1 (Ddit4/REDD1), a stress-responsive inhibitor of mammalian target of rapamycin complex 1 (mTORC1). Using a mouse model and differentiated C2C12 myotubes, we examined ER stress signaling, protein synthesis, and mTORC1 activity following cisplatin treatment, and evaluated the effects of tauroursodeoxycholic acid (TUDCA), an ER stress-suppressing chemical chaperone. Cisplatin induced skeletal muscle atrophy accompanied by ER stress activation and suppression of protein synthesis in mice. TUDCA significantly attenuated muscle mass and strength loss without affecting body weight reduction. Cisplatin upregulated ER stress-responsive genes and decreased phosphorylation of p70 S6 kinase, whereas these changes were suppressed by TUDCA. Pharmacological ER stress induction increased Ddit4/REDD1 expression, and PERK inhibition reduced cisplatin-induced Ddit4/REDD1 upregulation in C2C12 myotubes. Furthermore, Ddit4/REDD1 knockdown partially restored protein synthesis and mTORC1 signaling. These findings indicate that cisplatin induces skeletal muscle atrophy via ER stress-associated translational suppression, at least partly through Ddit4/REDD1-mediated inhibition of mTORC1.

Keywords:  Cisplatin; Ddit4/REDD1; ER stress; Muscle atrophy; mTORC1

DOI:  https://doi.org/10.1016/j.cbi.2026.112260
Nucleic Acids Res. 2026 Jul 17. pii: gkag736. [Epub ahead of print]54(14):

Toward a comprehensive modification landscape of yeast mitochondrial tRNAs using Nanopore direct RNA sequencing and dihydrouridine sequencing.

Julia L Reinsch, David M Garcia.

Saccharomyces cerevisiae is an invaluable model in the study of mitochondrial tRNA biology. Yet the positions of modified bases in all yeast mitochondrially encoded tRNAs (mt-tRNAs) are still not fully mapped. We performed Nanopore direct RNA sequencing (DRS) on tRNAs from the crude mitochondrial fraction of yeast to map base modifications across all 24 mt-tRNA isoacceptors. Additionally, we adapted the "D-seq" method to detect dihydrouridine sites in tRNAs, where chemical reduction of dihydrouridine causes disruptions to reverse transcription. We mapped dihydrouridine, pseudouridine, and N2-dimethylguanosine sites in mt-tRNAs using DRS, tRNA-D-seq, and knockouts of five conserved tRNA-modifying enzymes. Our results establish Dus1 and Dus2 as the enzymes responsible for D14, D16, D17, D17a, and D20 formation in S. cerevisiae mt-tRNAs. We provide evidence of interactions between Dus1, Dus2, and Trm1-catalyzed modifications, and the influence of Ψ55 promoting m5U54 in mt-tRNAs. These findings expand our understanding of mt-tRNA base modifications and their interdependence, and advance opportunities for the yeast model to investigate defects in human mt-tRNA function.

DOI: https://doi.org/10.1093/nar/gkag736
J Nat Med. 2026 Jul 20.

Quercetin attenuates cisplatin-induced muscle atrophy via Hippo/YAP1 signaling pathway.

Jingchun Lv, Jianwei Lin, Xiaojing Chen, Qi Wu, Zhiyao Cao, Dapeng Jiang.

  Muscle wasting is a common event among cancer patients receiving chemotherapy treatment and has been reported to affect their survival. However, current therapies for counteracting this side effect are ineffective. This study investigates quercetin's efficacy against cisplatin-induced muscle atrophy and its mechanism. Using both C2C12 myotube and mouse models, we found quercetin pretreatment significantly alleviates cisplatin-induced muscle wasting. Mechanistically, transcriptome analysis identified that the Hippo signaling pathway was involved in cisplatin-induced muscle atrophy. Quercetin restored the activity of this pathway, including the expression and nuclear localization of its effector YAP1. Furthermore, quercetin mitigated cisplatin-induced muscle damage by improving mitochondrial membrane quality and function. Molecular docking revealed a direct interaction between quercetin and YAP1. Additionally, the possible interaction between YAP1 and mitochondrial function was revealed. Our findings demonstrate that quercetin attenuates cisplatin-induced muscle atrophy by modulating the Hippo/YAP1 pathway and preserving mitochondrial homeostasis, highlighting its therapeutic potential.

Keywords:  Cisplatin; Mitochondrial dysfunction; Muscle atrophy; Quercetin; YAP1

DOI:  https://doi.org/10.1007/s11418-026-02062-1
Cell Rep. 2026 Jul 18. pii: S2211-1247(26)00781-3. [Epub ahead of print]45(7): 117703

TTYH3 regulates a lysosomal chloride conductance and controls lysosomal fusion, autophagy and senescence.

Jiamin Huang, Yayu Wang, Yudong Xu, Yanan Wei, Xiang Yin, Junling Li, Yu Zeng, Meiting Chen, Canjun Li, Li Wang, Xiaomei Li, Lili Qu, Chunlei Cang.

  Chloride is the most abundant anion within lysosomes and plays a pivotal role in regulating lysosomal physiology and function. However, the mechanisms governing lysosomal chloride homeostasis remain largely elusive. Here, we identified TTYH3 as a regulator of lysosomal chloride permeability. TTYH3 mediates chloride efflux from the lysosomal lumen and enhances TRPML1-mediated lysosomal calcium release. Overexpression of TTYH3 results in markedly enlarged lysosomes by promoting lysosomal fusion via the Ca2+/CaM and HSP90 pathways. Moreover, TTYH3 enhances autophagy by inhibiting the AKT/mTOR signaling pathway and alleviates cellular senescence via activation of the ERK pathway. Notably, TTYH3 expression mitigates cellular phenotypes associated with lysosomal storage diseases caused by deficiencies in another lysosomal chloride channel CLN7. Collectively, our findings demonstrate that TTYH3 mediates a lysosomal chloride conductance and regulates lysosomal physiology and autophagy, and may serve as a potential therapeutic target for interventions in aging and lysosome-related diseases.

Keywords:  CLN7; CP: molecular biology; ERK; HSP90; TTYH3; autophagy; chloride conductance; lysosome; lysosome fusion; mTOR; senescence

DOI:  https://doi.org/10.1016/j.celrep.2026.117703
Physiol Res. 2026 Jul 22. 75(3): 569-584

The Injection of miR-1/133 Antagonist Notably Accelerated the Healing Process of Exercise-Induced Skeletal Muscle Injury.

X Liu, M Yuan, N Zhang, J Xing.

Exercise-induced muscle damage (EIMD) significantly impacts daily work and life. The rapid promotion of repair for EIMD is worthy of attention. This study aimed to investigate the effect and mechanism of microRNAs in treating EIMD. By establishing an acute skeletal muscle injury model, we determined the key time point for skeletal muscle injury repair and the time-specific changes in MRTF-A/Pax7/SRF and muscle regeneration factors during the repair process. MicroRNAs antagonists were injected to verify the targeting relationship between miR-1/133a and MRTF-A/Pax7/SRF. A single bout of acute eccentric exercise caused significant damage to the morphological ultrastructure of rat gastrocnemius muscles, with the most severe injuries occurring 72 h after exercise. At this particular time point, it was identified as crucial for damage repair. Both miR-1-3p and miR-133a-3p collectively targeted and suppressed the protein translation of MRTF-A, Pax7, and SRF. Furthermore, both miR-1-3p and miR-133a-3p antagonists targeted the MRTF-A/Pax7 axis as well as the MRTF-A/SRF axis. MiR-1-3p antagonists primarily promote muscle proliferation and differentiation, while miR-133a-3p antagonists mainly promote differentiation while inhibiting atrophy. Combined injection effectively promote both muscle proliferation and differentiation while inhibiting atrophy, thereby facilitating damage repair in skeletal muscle fiber structure. Key words Exercise " Muscle damage " Skeletal muscle regeneration " MRTF-A " Pax7 " SRF.
Pharmacol Res. 2026 Jul 19. pii: S1043-6618(26)00260-4. [Epub ahead of print] 108345

Rethinking frailty as a disorder of mitochondrial adaptability, from energetic congestion to systemic vulnerability.

Rebecca De Lorenzo, Patrizia Rovere-Querini.

  Frailty is a clinical syndrome of reduced physiological reserve in older adults for which no pharmacological treatment exists and whose cellular basis remains incompletely defined. As life expectancy rises without a comparable extension of healthspan, the absence of a mechanistic account able to guide targeted intervention is a growing clinical problem. The dominant model of primary mitochondrial bioenergetic insufficiency does not accommodate several features of the phenotype. Among the conditions most strongly associated with frailty in aging, obesity, particularly when coupled with sarcopenia, stands out for its rising prevalence and the depth of its systemic metabolic consequences. Drawing on a recent multi-omics characterisation of skeletal muscle in sarcopenic obesity and on the convergent literature in aging metabolism, organelle communication, and redox biology, we propose a complementary framework in which the proximate cellular abnormality of frailty is energetic congestion, a chronic mismatch between substrate input, energetic demand, and the capacity to dispatch the resulting flux through demand-driven oxidative metabolism. In this view the mitochondrion is not failing because fuel is scarce, but because energetic demand declines below the rate at which substrate continues to be delivered, so that substrate persists in relative rather than absolute excess, while mitochondrial adaptability is progressively impaired. The resulting cycle is self-amplifying, anchored in reverse electron transport, and generalises across skeletal muscle, adipose tissue, liver, heart and brain. Strategies that re-engage demand-driven metabolic flux through AMPK activation, substrate restriction, mild mitochondrial uncoupling, modulation of endoplasmic reticulum stress, and clearance of irreversibly congested cells are predicted to produce more durable benefits than energy supplementation, with structured exercise as the prototype of demand-driven recoupling. This perspective offers a path toward a precision pharmacology of frailty grounded in molecular stratification of patients.

Keywords:  Aging; Energetic congestion; Frailty; Mitochondrial dysfunction; Pharmacology of aging; Sarcopenia

DOI:  https://doi.org/10.1016/j.phrs.2026.108345
Muscles. 2026 Jul 12. pii: 50. [Epub ahead of print]5(3):

Exploring the Relationship Between Skeletal Muscle Mass and Muscle Strength in the Limbs of Elite Soccer Players.

Valentina Cavedon, Chiara Milanese, Carlo Zancanaro.

  Understanding the direct relationship between skeletal muscle mass and strength in athletes is paramount for optimizing performance. Such a relationship has been poorly investigated in soccer players. In this work, a large number (n = 225) of elite soccer players aged 14-37 years had whole-body (WB) and regional skeletal muscle mass (SMM) estimated from Dual-energy X-ray absorptiometry (DXA) scans, together with maximal isokinetic strength of several muscle groups. Results showed a statistically significant (p < 0.001) correlation between limb SMM or muscle strength and body mass (r = 0.84-0.86; r = 0.61-0.97, respectively) and stature (r = 0.58-0.64; r = 0.61-0.93, respectively), whereas the relationship with age was much more variable. A statistically significant (p < 0.001) correlation was found between SMM and muscle strength across all muscle groups (r = 0.55-0.80). Linear regression showed that SMM explained 30% to 64% of the variance in muscle strength. ANOVA showed that playing position had a statistically significant effect (p < 0.001) on all SMM and muscle strength values. Playing position had a significant effect on relative (normalized per-limb SMM) muscle strength during knee and ankle flexion. This work showed that DXA-measured skeletal muscle mass is associated with the strength of several limb muscle groups in soccer players. This association is of variable strength across muscle groups and is partially modulated by playing position.

Keywords:  arms; dual-energy X-ray absorptiometry; football; legs; strength

DOI:  https://doi.org/10.3390/muscles5030050
Clin Nutr ESPEN. 2026 Jul 20. pii: S2405-4577(26)00699-6. [Epub ahead of print]75 103602

Nutritional support for cancer cachexia: A systematic review and meta-analysis of randomized controlled trials.

Lucas Porto Santos, Bruno Gualano, Miriam López-Teros, Gersiel Oliveira-Junior, Igor Longobardi, Patrícia Puccetti Pires, Helen Vidaña Espinoza, Olga Laura Sena Almeida, Eduardo Ferriolli, Hamilton Roschel.

   BACKGROUND & AIMS: Cancer cachexia is a debilitating syndrome associated with poor prognosis. Nutritional support is a cornerstone of management, but its effectiveness remains uncertain due to inconsistent evidence. We synthesized the effects of nutritional support on key outcomes in patients with cancer cachexia.
METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), following PRISMA guidelines (PROSPERO: CRD42024570706). We searched four electronic databases for RCTs evaluating any nutritional support in adults with cancer cachexia. Outcomes included body weight and body composition, biochemical markers, handgrip strength, quality of life, and appetite. A random-effects model pooled the data, reported as mean differences (MD) or standardized mean differences (SMD).
RESULTS: 32 RCTs were included. Nutritional support was associated with modest increases in body weight (MD: 1.43 kg; 95% CI: 0.55-2.31 kg), fat-free mass (MD: 1.11 kg; 95% CI: 0.16-2.05 kg), fat mass (MD: 1.00 kg; 95% CI: 0.41-1.59 kg) and C-reactive protein (MD: -1.47 mg/L; 95% CI -2.55 to -0.39). However, CRP results were not robust in sensitivity analysis. No effects were observed handgrip strength, albumin, transferrin, quality of life, or appetite. The evidence base was limited by a predominant high risk of bias across the included studies.
CONCLUSIONS: Nutritional support in patients with cancer cachexia provides small body composition improvements. However, most body composition measures were performed through bioimpedance assessments, which limits their robustness. Additionally, this approach seem insufficient to reverse metabolic alterations or improve function alone. The certainty of this evidence highlights the need for higher quality, rigorously conducted trials.

Keywords:  Body composition; Cachexia; Meta-analysis; Muscle wasting; Nutrition; Quality of life

DOI:  https://doi.org/10.1016/j.clnesp.2026.103602
Elife. 2026 Jul 20. pii: RP106692. [Epub ahead of print]14

FMRP regulates neuronal RNA granules containing stalled ribosomes, not where ribosomes stall.

Jewel T-Y Li, Mehdi Amiri, Senthilkumar Kailasam, Lily Drever, Jingyu Sun, Laura Bohorquez, Nahum Sonenberg, Joaquin Ortega, Wayne S Sossin.

  Local protein synthesis is a crucial process that maintains local proteostasis in neurons. A large percentage of mRNAs translated in developing neurons are associated with stalled ribosomes. FMRP, the protein lost in Fragile X syndrome, is highly enriched in RNA granules that contain stalled ribosomes. Previous examination of ribosome-protected fragments (RPFs) from stalled neuronal ribosomes identified sequences that match those found in mRNAs associated with FMRP. To investigate whether FMRP recognition of these sequences is important for determining where ribosomes stall on mRNAs, we examined RPFs isolated from P5 mice of both sexes that lack the FMRP protein. The loss of FMRP had no significant effect on the proteins associated with neuronal stalled ribosomes, on ribosome structure, or the stalling sites (locations where RPFs accumulated). There was a small, but significant decrease in the number of RPFs from mRNAs previously shown to be associated with FMRP by CLIP. Additionally, the number of neuronal RNA granules containing stalled ribosomes, as assayed by ribopuromycylation, decreased. These results suggest a role of FMRP in neuronal RNA granules that contain stalled ribosomes, though loss of FMRP does not influence where ribosomes are stalled or the formation of stalled ribosome.

Keywords:  FMRP; RNA binding protein; RNA granule; cell biology; mouse; neuroscience; ribopuromycylation; ribosome-protected fragment; stalled ribosome

DOI:  https://doi.org/10.7554/eLife.106692