bims-musmir 2025-10-26 papers

Toxicol Appl Pharmacol. 2025 Oct 17. pii: S0041-008X(25)00380-1. [Epub ahead of print]505 117604

Corylifol A ameliorates pancreatic cancer-associated cachexia by targeting TAOK3 in pancreatic cancer cells and targeting TAOK1 in skeletal muscle cells.

Ke Yu, Rui-Qin Zhang, Nan Li, Qiong-Sen Wang, Jia Gu, Sai-Yue He, Ying-Qian Wang, Guo-Guo Wang, Xiong-Wen Zhang, Xiao-Dong Guo, Xuan Liu.

As many as 80 % of pancreatic cancer patients might suffer from cancer cachexia, a distressing condition characterized by involuntary weight loss and muscle wasting. Regrettably, there remains an insufficiency of efficacious pharmacological interventions for the management of cancer cachexia. The effectiveness of corylifol A (CYA) in treating pancreatic cancer-associated cachexia was assessed, and its underlying mechanisms were examined in the present study. Cultured C2C12 myotubes induced with conditioned medium from MiaPaCa-2 pancreatic cancer cells (MIA CM) were utilized as an in vitro model to investigate the impact of CYA on muscle atrophy associated with cancer cachexia. The MIA cachexia mice model was utilized to evaluate the in vivo impact of CYA on cancer cachexia. CYA (2.5, 5, and 10 μM) dose-dependently mitigated MIA CM-induced myotube atrophy through targeting the thousand and one amino acid protein kinase 1 (TAOK1) and blocking protein degradation via the ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP). Importantly, CYA (10 mg/kg/d, i.p.) not only significantly ameliorated weight loss and muscle atrophy but also inhibited the tumor growth in MIA cancer cachexia mice. In pancreatic cancer cells, CYA directly targets the thousand and one amino acid kinase 3 (TAOK3). Both knockdown and overexpression of TAOK3 could alleviate the cytotoxicity of CYA on pancreatic cancer cells. Collectively, CYA ameliorated pancreatic cancer-associated cachexia by targeting TAOK1 in skeletal muscle cells as well as targeting TAOK3 in pancreatic cancer cells.

Keywords: Cancer cachexia; Corylifol A; Muscle atrophy; Pancreatic cancer; TAOK1; TAOK3

DOI: https://doi.org/10.1016/j.taap.2025.117604

Am J Physiol Cell Physiol. 2025 Oct 24.

Sex impacts inflammatory signaling, body composition, and physical function in tumor-bearing mice receiving chemotherapy.

Jessica L Halle, Quan Zhang, Dryden R Baumfalk, Melissa J Puppa, Junaith S Mohamed, Evan S Glazer, Ashley J Smuder, Stephen E Alway, James A Carson.

Cancer-induced inflammation has been widely investigated as a driver of cachexia, and sex can affect the inflammatory response to cancer. We have an incomplete understanding of how anti-cancer treatments and sex impact the relationship between inflammatory responses and changes to body composition and physical function during cancer treatment. We investigated the effect of FOLFOX chemotherapy (5-fluorouracil, leucovorin, oxaliplatin) on circulating inflammatory cytokines, body composition, and physical function in CT26 tumor-bearing male and female mice. BALB/c mice were injected with CT26 tumor cells, and after the tumor was palpable, underwent three cycles of FOLFOX. FOLFOX reduced tumor mass in both sexes. CT26 induced plasma IL-6, LIF, and TNF-α in males and females. FOLFOX attenuated the CT26-induced IL-6 and LIF levels in males, but in females FOLFOX alone induced IL-6 and TNF-α, and did not attenuate their CT26 induction. In CT26 males, but not females, total lean and hindlimb mass were negatively associated with IL-6, and FOLFOX disrupted this association. The CT26-induced muscle p-STAT3 was inversely associated with muscle mass in males only and disrupted by FOLFOX. Circulating inflammatory cytokines were associated with body composition changes and functional deficits in CT26 males, but FOLFOX and female sex altered this relationship. Our results provide evidence that the female response to circulating inflammatory cytokines in the CT26 tumor environment, following FOLFOX chemotherapy, differs from that of males, and the physiological ramifications of this regulation warrant further investigation.

Keywords: FOLFOX; Interleukin-6 (IL-6); colorectal cancer; leukemia inhibitory factor (LIF); signal transducer and activator of transcription 3 (STAT3)

DOI: https://doi.org/10.1152/ajpcell.00643.2025

Clin Rheumatol. 2025 Oct 20.

Health-enhancing physical activity induce beneficial skeletal muscle mitochondrial adaptations in individuals with rheumatoid arthritis.

Emily Shorter, Elena Ossipova, Estela Santos Alves, Helena Idborg, Jone Vanluyten, Eva Kosek, Liu Zhengye, Birgitta Nordgren, Cecilia Fridén, Ferdinand von Walden, Christer Malm, Per-Johan Jakobsson, Christina H Opava, Marina Korotkova, Ingrid E Lundberg, Johanna T Lanner.

OBJECTIVE: Rheumatoid arthritis (RA) is a common chronic systemic inflammatory disease that causes musculoskeletal impairments and fatigue. Physical activity is recommended for individuals with RA, and health-enhancing physical activity (HEPA) has been shown to improve health perception and physical fitness in this group. However, the molecular adaptations of skeletal muscle in response to an exercise intervention are still unexplored in individuals with RA. This study aimed to assess the skeletal muscle response to a 2-year HEPA intervention in individuals with RA.
METHODS: Thirteen individuals with RA (65 ± 2 years old, 13 ± 2 years disease duration) participated. The 2-year HEPA intervention involved 150 min of weekly moderately intense aerobic activity and twice-weekly circuit training. Practical and theoretical physiotherapist support was available the first year, but not the second year. Skeletal muscle biopsies, functional assessments, and mass spectrometry-based proteomics analysis were conducted.
RESULTS: Compliance was high the first year but dropped significantly the second year. Functional improvements in strength, endurance, and lower extremity muscle function (TST) were observed after year 1. Proteomics analysis revealed significant enrichment of mitochondrial proteins including COX8A, citrate synthase, M2OM, NDUFA6, NDUFS2, and VDAC3 after year 1, indicating positive muscle adaptations. However, these changes regressed to baseline levels by year 2.
CONCLUSION: HEPA can induce beneficial mitochondrial adaptations in skeletal muscle of individuals with RA. However, insufficient compliance and progression in HEPA exercise load led to a reversal of these adaptations. Continuous support and motivation are crucial for maintaining and progressing exercise levels and muscle health in individuals with RA. Key points • Health-enhancing physical activity (HEPA) can induce beneficial mitochondrial adaptations in the skeletal muscle proteome of individuals with RA. • Positive effects on mitochondrial protein levels aligned with the participants compliance to the HEPA intervention. • Results emphasizes that sustaining and progressing exercise regimen is crucial to maintain beneficial adaptations for individuals with RA.

Keywords: Exercise adaptation; Health-enhancing physical activity; Mitochondria; Muscle biopsy; Rheumatoid arthritis; Skeletal muscle

DOI: https://doi.org/10.1007/s10067-025-07734-z

Cell Commun Signal. 2025 Oct 22. 23(1): 452

Lamin A/C protects chromatin accessibility during mechanical loading in human skeletal muscle.

Saline Jabre, Emeline Cherchame, Natalia Pinzón, Eline Lemerle, Marc Bitoun, Catherine Coirault.

BACKGROUND: Skeletal muscle nuclei (myonuclei) are subjected to high mechanical stress which plays a critical role in muscle tissue integrity and plasticity. Here we investigated the role of lamin A/C in dampening the effects of acute mechanical stretch on chromatin states and its downstream effects on gene expression.
METHODS: We studied control and lamin A/C-deficient human myotubes both at baseline and following a mechanical stress mimicking acute muscle exercise. Chromatin accessibility and transcriptional responses were assessed using ATAC-seq (assay for transposase-accessible chromatin with sequencing) and RNA-seq, respectively.
RESULTS: We found that stretch-induced nuclear deformations in lamin A/C-deficient myotubes but not in controls, and was associated with a widespread increase in chromatin accessibility, mainly affecting promoter regions. Concordantly, mechanical stress also increased the levels of H3K4me3 euchromatin marks and decreased heterochromatin-associated H3K27me3 in A-type lamin-deficient myotubes. Additionally, mechanical stress led to the downregulation of transcriptional pathways involved in histone deacetylation, DNA methylation, and muscle differentiation, while pathways related to cytokine activity, extracellular matrix organization, and cell adhesion were upregulated.
CONCLUSIONS: Overall, lamin A/C deficiency amplifies the chromatin response to mechanical stress, leading to enhanced promoter accessibility and activation of stress DNA damage-related gene pathways. These findings underscore the role of lamin A/C in maintaining chromatin stability under mechanical strain.

Keywords: Chromatin; Lamins; Mechanical loading; Muscle cells; Nuclear mechanotransduction

DOI: https://doi.org/10.1186/s12964-025-02437-z

Cell Rep. 2025 Oct 16. pii: S2211-1247(25)01218-5. [Epub ahead of print]44(10): 116447

Heat shock induces silent ribosomes and reorganizes mRNA turnover.

Sayanur Rahaman, Nicole Schiffelholz, Nitish Mittal, Klemens E Fröhlich, Mihaela Zavolan, Attila Becskei.

mRNAs associate with single or multiple ribosomes; these ribosomal assemblies-monosomes and polysomes-translate the mRNAs before degradation. The impact of heat stress on this mRNA turnover remains unclear. We show that in heat-shocked yeast cells, the proportion of monosomes increases without a corresponding rise in the number of associated mRNAs. Consequently, most monosomes are devoid of mRNAs and silent, lacking translational initiation factors and proteins facilitating posttranslational folding. Such silent monosomes also appear under other stress conditions, with proportions varying according to stress type, suggesting that they represent a general feature of cellular adaptation. In parallel with the induction of silent ribosomes, elevated temperatures reduce the overall rate of mRNA-ribosome association with few exceptions. Notably, heat shock promotes the ribosomal association of transcripts encoding heat shock proteins, without extension of the half-lives of these mRNAs. These mechanisms dynamically reorganize mRNA turnover to prioritize the translation of heat shock proteins over other proteins.

Keywords: 4-thiouracil; CP: Genomics; CP: Molecular biology; Saccharomyces cerevisiae; codon optimality; mRNA half-life; mRNA metabolic labelling; macrophage; polysome profiling; proteomics; stress granule; xrn1

DOI: https://doi.org/10.1016/j.celrep.2025.116447

Stem Cell Reports. 2025 Oct 23. pii: S2213-6711(25)00288-7. [Epub ahead of print] 102684

Delineating transcriptomic signatures of in vitro human skeletal muscle models in comparison to in vivo references.

Margaux Van Puyvelde, Eslam Essam Mohammed, Ángela Moreno Anguita, Jarne Bonroy, Sandra Jansen, Atilgan Yilmaz.

A pivotal question at the heart of stem cell research is how faithful cellular models recapitulate human tissues. Skeletal muscle, the largest organ in the human body, has been modeled by various in vitro systems. Here, we sought to delineate the state-of-the-art of muscle models by performing a large-scale analysis of transcriptome datasets, covering over 400 samples across 39 studies, including bulk and single-cell RNA sequencing of 2D and 3D models and their in vivo counterparts. By comparing these models to in vivo muscle, we highlighted failed upregulation of myogenic factors and retention of epigenetic memory from the in vitro source material. We featured differences in lipid metabolism and depletion of multiple fibroblast growth factor (FGF) ligands in the in vitro models. Finally, we revealed model-dependent variation in myogenic progenitors. Our analyses highlight targetable processes to improve the models while paving the way for similar studies on other cell types.

Keywords: bulk RNA sequencing; in vitro models; single cell RNA sequencing; skeletal muscle; skeletal muscle differentiation; skeletal muscle transdifferentiation; transcriptomics

DOI: https://doi.org/10.1016/j.stemcr.2025.102684