bims-musmir 2025-05-18 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–05–18
seven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Cancer-induced FOXP1 disrupts and reprograms skeletal-muscle circadian transcription in cachexia.
Muscle-specific kinase levels in blood are an early diagnostic biomarker for SOD1-93A mouse model of ALS.
Neuromuscular junction transcriptome analysis of spinal and bulbar muscular atrophy mice implicates sarcomere gene expression and calcium flux dysregulation in disease pathogenesis.
Identification of a resistance-exercise-specific signalling pathway that drives skeletal muscle growth.
Iron Metabolism and Muscle Aging: Where Ferritinophagy Meets Mitochondrial Quality Control.
Unacylated Ghrelin Counteracts Contractile and Mitochondrial Dysfunction in Cancer Cachexia.
Randomized Phase II Study of Nab-Paclitaxel and Gemcitabine With or Without Tocilizumab as First-Line Treatment in Advanced Pancreatic Cancer: Survival and Cachexia.

Cell Rep. 2025 May 10. pii: S2211-1247(25)00460-7. [Epub ahead of print]44(5): 115689

Cancer-induced FOXP1 disrupts and reprograms skeletal-muscle circadian transcription in cachexia.

Jeremy B Ducharme, Daria Neyroud, Martin M Schonk, Miguel A Gutierrez-Monreal, Zhiguang Huo, Haley O Tucker, Karyn A Esser, Sarah M Judge, Andrew R Judge.

  Cancer cachexia is a debilitating metabolic disorder characterized by involuntary loss of body and muscle mass, leading to increased morbidity and mortality. We previously found that forkhead box P1 (FoxP1) upregulation in skeletal muscle causes muscle wasting and is required for muscle wasting in response to cancer. However, transcriptional networks targeted by FoxP1 in skeletal muscles undergoing cancer-induced wasting remain largely unknown. Here, we identify FoxP1 as a key disruptor of the skeletal-muscle clock in response to cancer that reprograms circadian patterns of gene expression at cachexia onset. Specifically, we show that cancer-induced FoxP1 rewires the skeletal-muscle circadian transcriptome toward pathways associated with muscle wasting and disrupts the temporal patterning of pathways governing glucose, lipid, and oxidative metabolism. These findings thus implicate cancer/disease-specific functions of FOXP1 in the disruption and reprograming of the skeletal-muscle circadian transcriptome, which may contribute to muscle wasting and the development of cachexia.

Keywords:  CP: Cancer; ChIP-seq; RNA-seq; cancer cachexia; circadian rhythm; inflammation; metabolism; muscle atrophy; muscle clock; pancreatic cancer; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2025.115689
Front Neurol. 2025 ;16 1556120

Muscle-specific kinase levels in blood are an early diagnostic biomarker for SOD1-93A mouse model of ALS.

Shuuichi Mori, Heying Zhou, Takuya Omura, Hiroki Tsumoto, Yuri Miura, Kazuhiro Shigemoto.

  Neuromuscular junction (NMJ) denervation is an early event preceding motor neuron loss in amyotrophic lateral sclerosis (ALS). Progressive loss of the NMJ leads to irreversible muscle weakness and atrophy. Muscle-specific kinase (MuSK), locally expressed at the postsynaptic membrane of the NMJ, is activated by agrin released from motor nerve terminals and is essential for NMJ maintenance and regeneration. Here, we found that the progression of NMJ denervation prior to the onset of muscle weakness in SOD1-93A mouse model of ALS correlated with increased serum MuSK immunoreactivity and elevated MuSK expression throughout the skeletal muscle. Our results suggest that neuromuscular failure associated with the onset of muscle weakness increases MuSK expression throughout the muscle, which is subsequently cleaved by proteolytic enzymes to increase MuSK immunoreactivity in the blood. These results demonstrate that the level of serum MuSK immunoreactivity may indicate the early phase of NMJ denervation and serve as a biomarker for assessing the progression of other types of ALS and therapeutic benefits in preclinical studies.

Keywords:  MuSK; NMJ; SOD1 mouse G93A; biomarker; diagnosis; mouse model

DOI:  https://doi.org/10.3389/fneur.2025.1556120
Hum Mol Genet. 2025 May 14. pii: ddaf074. [Epub ahead of print]

Neuromuscular junction transcriptome analysis of spinal and bulbar muscular atrophy mice implicates sarcomere gene expression and calcium flux dysregulation in disease pathogenesis.

Anastasia Gromova, Byeonggu Cha, Nhat Nguyen, Diya Garg, Connor Coscolluela, Laura M Strickland, David Luong, Fabiana Longo, Bryce L Sopher, Mai K ElMallah, Albert R La Spada.

  X-linked Spinal and Bulbar Muscular Atrophy (SBMA) is a rare, late-onset neuromuscular disease caused by a CAG repeat expansion mutation in the androgen receptor (AR) gene. SBMA is characterized by progressive muscle atrophy of both neurogenic and myopathic etiologies. Previous work has established that mutant AR expression in skeletal muscle could be a significant contributor to neuromuscular decline, yet the mechanisms involved remain ill-defined. As AR is a nuclear hormone receptor transcription factor, we sought to define early changes in gene expression in skeletal muscle of pre-symptomatic SBMA mice, with a focus on transcriptional changes at the neuromuscular junction (NMJ). We describe loss of key NMJ-specific genes in synaptic muscle regions of pre-symptomatic SBMA mice, while extrasynaptic muscle features a coordinated loss of sarcomere genes that coincides with ectopic re-expression of certain NMJ genes. Furthermore, SBMA muscle prominently features dysregulated calcium flux, likely stemming from a compensatory response to early atrophy that greatly exacerbates over time. The SERCA activator CDN1163 conferred a mild rescue in function and muscle size in SBMA mice, while genetic deletion of the gene encoding Myf6/MRF4, a negative regulator of sarcomere gene expression and predicted AR interactor, did not ameliorate muscle atrophy. These studies suggest that modulation of calcium flux could be a promising pharmacological target in SBMA.

Keywords:  androgen receptor; motor neuron disease; neuromuscular junction; spinal and bulbar muscular atrophy; transcriptome

DOI:  https://doi.org/10.1093/hmg/ddaf074
Nat Metab. 2025 May 15.

Identification of a resistance-exercise-specific signalling pathway that drives skeletal muscle growth.

Wenyuan G Zhu, Aaron C Q Thomas, Gary M Wilson, Chris McGlory, Jamie E Hibbert, Corey Gk Flynn, Ramy K A Sayed, Hector G Paez, Marius Meinhold, Kent W Jorgenson, Jae-Sung You, Nathaniel D Steinert, Kuan-Hung Lin, Martin J MacInnis, Joshua J Coon, Stuart M Phillips, Troy A Hornberger.

Endurance and resistance exercise lead to distinct functional adaptations: the former increases aerobic capacity and the latter increases muscle mass. However, the signalling pathways that drive these adaptations are not well understood. Here we identify phosphorylation events that are differentially regulated by endurance and resistance exercise. Using a model of unilateral exercise in male participants and deep phosphoproteomic analyses, we find that a prolonged activation of a signalling pathway involving MKK3b/6, p38, MK2 and mTORC1 occurs specifically in response to resistance exercise. Follow-up studies in both male and female participants reveal that the resistance-exercise-induced activation of MKK3b is highly correlated with the induction of protein synthesis (R = 0.87). Additionally, we show that in mice, genetic activation of MKK3b is sufficient to induce signalling through p38, MK2 and mTORC1, along with an increase in protein synthesis and muscle fibre size. Overall, we identify core components of a signalling pathway that drives the growth-promoting effects of resistance exercise.

DOI: https://doi.org/10.1038/s42255-025-01298-7
Cells. 2025 May 03. pii: 672. [Epub ahead of print]14(9):

Iron Metabolism and Muscle Aging: Where Ferritinophagy Meets Mitochondrial Quality Control.

Rosa Di Lorenzo, Emanuele Marzetti, Helio José Coelho-Junior, Riccardo Calvani, Vito Pesce, Francesco Landi, Christiaan Leeuwenburgh, Anna Picca.

  In older adults with reduced physical performance, an increase in the labile iron pool within skeletal muscle is observed. This accumulation is associated with an altered expression of mitochondrial quality control (MQC) markers and increased mitochondrial DNA damage, supporting the hypothesis that impaired MQC contributes to muscle dysfunction during aging. The autophagy-lysosome system plays a critical role in MQC by tagging and engulfing proteins and organelles for degradation in lysosomes. The endolysosomal system is also instrumental in transferrin recycling, which, in turn, regulates cellular iron uptake. In the neuromuscular system, the autophagy-lysosome system supports the structural integrity of neuromuscular junctions, and its dysfunction contributes to muscle atrophy. While MQC was thought to protect against iron-induced cell death, the discovery of ferroptosis, a form of iron-dependent cell death, has highlighted a complex interplay between MQC and iron-inflicted damage. Ferritinophagy, the autophagic degradation of ferritin, if overactivated, can induce ferroptosis. Alternatively, aging may impair ferritinophagy, leading to ferritin accumulation and the release of toxic labile iron under stress, exacerbating oxidative damage and cellular senescence. Physical activity supports muscle health also by preserving mitochondrial quantity and quality and enhancing bioenergetics. However, therapeutic strategies for preventing or reversing physical function decline in aging are still lacking due to the insufficient understanding of the underlying mechanisms. Unveiling how disruptions in iron homeostasis impact muscle quality in older adults may allow for the development of therapeutic strategies targeting iron handling to alleviate age-associated muscle decline.

Keywords:  autophagy; cytokine; endolysosomal system; hepcidin; inflammation; labile iron; mitophagy; physical performance; sarcopenia; transferrin

DOI:  https://doi.org/10.3390/cells14090672
bioRxiv. 2025 May 04. pii: 2025.04.29.649515. [Epub ahead of print]

Unacylated Ghrelin Counteracts Contractile and Mitochondrial Dysfunction in Cancer Cachexia.

Bumsoo Ahn, Jonathan Wanagat, Caroline Cleary, Hannah C Ainsworth, Eunyoung Kim, Hyunyoung Kim.

Background: Cancer cachexia is a complex metabolic syndrome that severely impacts patient mobility, treatment strategies, and quality of life. However, no treatments are available to mitigate the debilitating consequences of cancer cachexia. Unacylated ghrelin (UnAG), the main circulating form of ghrelin, enhances muscle growth and mitochondrial function in various diseases, but its effects in cancer cachexia remain to be tested.
Methods: Male C57Bl6/N mice were assigned to one of three treatment groups: non-tumor-bearing (NTB), tumor-bearing (TB), or tumor-bearing treated with unacylated ghrelin (TB+UnAG). Over four weeks, we monitored body weight, food intake, and tumor size. We assessed muscle mass, contractility, mitochondrial oxygen consumption rate (OCR), and reactive oxygen species (ROS) production. Proteomic analysis was performed to elucidate the downstream effects of UnAG. Cell culture assays were performed to measure the in vitro effects of cancer cell-secreted factors and UnAG on myoblasts.
Results: Gastrocnemius and quadriceps muscle masses were reduced by 20-30% in TB mice compared to NTB controls; however, UnAG treatment prevented approximately 50% of this loss. Beyond muscle mass, UnAG enhanced the isometric maximum specific force of the extensor digitorum longus by 70% in TB mice. This improvement in muscle quality was associated with preferential upregulation of myosin heavy chain expression in TB+UnAG mice. UnAG also increased mitochondrial OCR while reducing ROS production. Mitochondrial DNA (mtDNA) copy number, which was reduced in TB mice, was restored by UnAG, while the reduced mtDNA mutation frequency in TB mice was maintained with treatment, indicating improved mtDNA integrity. Consistent with enhanced mitochondrial function, treadmill running time was significantly increased in TB+UnAG mice. Proteomic analysis revealed that UnAG downregulated proteins associated with proteolysis, while normalizing antioxidant enzyme thioredoxin and proteins involved in calcium handling. Cancer cell-conditioned medium reduced myotube width in vitro, but UnAG treatment preserved myotube structure..
Conclusion: UnAG protects against cancer cachexia by targeting multiple risk factors, including myosin heavy chain expression, mitochondrial bioenergetics, and modulation of protein degradation pathways.

DOI: https://doi.org/10.1101/2025.04.29.649515
J Clin Oncol. 2025 May 12. JCO2301965

Randomized Phase II Study of Nab-Paclitaxel and Gemcitabine With or Without Tocilizumab as First-Line Treatment in Advanced Pancreatic Cancer: Survival and Cachexia.

Inna M Chen, Julia S Johansen, Susann Theile, Libbie M Silverman, Katherine R Pelz, Kasper Madsen, Olav Dajani, Kevin Z M Lim, Torben Lorentzen, Omnia Gaafer, Leonidas G Koniaris, Anna C Ferreira, Brian Neelon, Denis C Guttridge, Michael C Ostrowski, Teresa A Zimmers, Dorte Nielsen.

PURPOSE: This randomized phase-II trial (ClinicalTrials.gov identifier: NCT02767557) compared efficacy of gemcitabine/nab-paclitaxel (Gem/Nab) with or without the anti-interleukin-6 (IL-6) receptor antibody tocilizumab (Toc) for advanced pancreatic cancer (PC).
METHODS: A safety cohort received Gem 1,000 mg/m2 and Nab 125 mg/m2 on days 1, 8, and 15, and Toc 8 mg/kg on day 1 for each 28-day cycle. Participants with modified Glasgow prognostic scores of 1 or 2 were randomly assigned 1:1 to receive Gem/Nab/Toc or Gem/Nab. The primary end point was the overall survival (OS) rate at 6 months (OS6). Secondary end points were progression-free survival (PFS), overall response rate (ORR), and safety. Exploratory end points were cachexia, quality of life, and biomarkers, including the cachexia-promoting protein, growth differentiation factor 15 (GDF15).
RESULTS: Overall, 147 patients were treated, including six safety cohort participants. The median follow-up period was 8.1 months (IQR, 4.2-13.9). OS6 was 68.6% (95% CI, 56.3 to 78.1) for the Gem/Nab/Toc group and 62.0% (49.6-72.1) for the Gem/Nab group (P = .409). OS for Gem/Nab/Toc versus Gem/Nab improved at 18 months (27.1% v 7.0%, P = .001). No differences in median OS, PFS, or ORR were observed. Incidence of grade-3+ treatment-related adverse events (TrAEs) was 88.1% for Gem/Nab/Toc and 63.4% for Gem/Nab (P < .001). Gem/Nab/Toc decreased muscle loss versus Gem/Nab, with median change +0.1013% versus -3.430% (P = .0012) at 2 months and +0.7044 versus -3.353% (P = .036) at 4 months. Incidence of muscle loss was 43.48% on Gem/Nab/Toc versus 73.52% on Gem/Nab at 2 months (P = .0045) and 41.82% versus 68.75% (P = .0062) at 4 months. GDF15 was not changed by Gem/Nab or Gem/Nab/Toc.
CONCLUSION: Although the primary end point was not met and TrAEs were increased by Toc, increased survival at 18 months and reduced muscle wasting support an anticachexia effect of IL-6 blockade independent of GDF15. Further studies could leverage these findings for precision anticachexia therapy.

DOI: https://doi.org/10.1200/JCO.23.01965