bims-musmir 2025-07-20 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–07–20
fifteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Targeting the canonical ER stress IRE1α/XBP1 pathway counteracts pancreatic cancer-induced skeletal muscle wasting.
Klotho deficiency promotes skeletal muscle weakness and is associated with impaired motor unit connectivity.
Impairment of P2 Receptor-Mediated Modulation of Skeletal Muscle Contractions in Transgenic Mice with Modeled Amyotrophic Lateral Sclerosis.
Skeletal muscle stem cell mitochondria are transferred to muscle fibers in response to a hypertrophic stimulus.
Kv3 channel agonist ameliorates the phenotype of a mouse model of amyotrophic lateral sclerosis.
Molecular constraints of sarcopenia in the ageing muscle.
m6A Methylation-Induced Autophagy Impairment by TFEB Regulation in SOD1-G93A ALS Cell Model.
Intramuscular CMT-167 Tumors Produce a Mild Cachexia Phenotype in C57BL/6J Mice.
Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations.
TDP-43 pathology induces CD8+ T cell activation through cryptic epitope recognition.
Targeting phospholipase PLAG-15 promotes healthy aging in C. elegans via lysosomal-related genes.
Cellular repressor of E1A-stimulated genes 1 enhances skeletal muscle performance through the stimulation of muscle differentiation and Akt-mTOR signaling pathway activation.
Impact of the ICU admission of patients with COVID-19 on the outcomes of patients without COVID-19 in the ICU: a retrospective cohort study.
Mitochondrial p32-mediated regulation of p-TBK1 affects the radiosensitivity of colorectal cancer.
Inhibition of AhR improves cortical bone and skeletal muscle function via preservation of neuromuscular junctions.

bioRxiv. 2025 May 05. pii: 2025.05.05.652304. [Epub ahead of print]

Targeting the canonical ER stress IRE1α/XBP1 pathway counteracts pancreatic cancer-induced skeletal muscle wasting.

Aniket S Joshi, Meiricris Tomaz da Silva, Anh Tuan Vuong, Bowen Xu, Ravi K Singh, Ashok Kumar.

Cancer-driven cachexia is a deleterious syndrome which involves progressive loss of skeletal muscle mass with or without fat loss, fatigue, and weakness that cannot be reversed by nutritional intake. Recent studies have shown deregulation of endoplasmic reticulum (ER)-induced unfolded protein response (UPR) pathways in skeletal muscles in various catabolic conditions, including cancer growth. However, the role of individual arms of the UPR in regulation of muscle mass remains poorly understood. Here, we demonstrate that the IRE1α/XBP1 arm of the UPR stimulates the activation of ubiquitin-proteasome system, autophagy, JAK-STAT3 signaling, and fatty acid oxidation in skeletal muscle of the KPC mouse model of pancreatic cancer cachexia. Furthermore, our results show that IRE1α/XBP1 pathway is a key contributor to cachexia as targeted ablation of XBP1 transcription factor in mouse skeletal muscle inhibits KPC tumor-induced muscle wasting. Transcriptionally active XBP1 protein binds to the promoter region of multiple genes whose products are involved in skeletal muscle wasting. Treatment of KPC tumor-bearing mice with 4µ8C, a small molecule IRE1α inhibitor, reverses cachexia-induced molecular changes and improves skeletal muscle mass and strength. Altogether, our study highlights that the IRE1α/XBP1 signaling axis mediates pancreatic cancer-induced muscle wasting and inhibition of this pathway could be a potential approach to mitigate muscle wasting in pancreatic cancer patients.

DOI: https://doi.org/10.1101/2025.05.05.652304
bioRxiv. 2025 Jun 17. pii: 2025.06.11.659129. [Epub ahead of print]

Klotho deficiency promotes skeletal muscle weakness and is associated with impaired motor unit connectivity.

Linda A Bean, Connor Thomas, Juan F Villa, Alexander J Fitt, Areli Jannes S Javier, Akanksha Agrawal, Hanna Whitney, Guilherme Nascimento Dos Santos, Kenneth E White, Joshua R Huot, Steven S Welc.

Muscle wasting and weakness are important clinical problems that impact quality of life and health span by restricting mobility and independence, and by increasing the risk for physical disability. The molecular basis for this has not been fully determined. Klotho expression is downregulated in conditions associated with muscle wasting, including aging, chronic kidney disease, and myopathy. The objective of this study was to investigate a mechanistic role for Klotho in regulating muscle wasting and weakness. Body weight, lean mass, muscle mass, and myofiber caliber were reduced in Klotho-deficient mice. In the tibialis anterior muscle of Klotho null mice, type IIa myofibers were resistant to changes in size, and muscle composition differed with a higher concentration of type IIb fibers to the detriment of type IIx fibers. Glycolytic enzymatic activity also increased. The composition of the soleus muscle was unaffected and myofiber caliber was reduced comparably in type I, IIa, and IIx fibers. Muscle contractile function declined in Klotho-deficient mice, as evidenced by reduced absolute twitch and torque, and decreased rates of contraction and relaxation. RNA-sequencing analysis identified increased transcriptional expression of synaptic and fetal sarcomeric genes, which prompted us to test effects on muscle innervation. Klotho-deficiency induced morphological remodeling of the neuromuscular junction, myofiber denervation, and a functional loss of motor units. Loss of motor units correlated with absolute torque. Collectively, our findings have uncovered a novel mechanism through which Klotho-deficiency leads to alterations to the muscle synapse affecting motor unit connectivity that likely influences muscle wasting and weakness.
Key points summary: Maintaining skeletal muscle mass and function is critical to preserve physical capacity and independence. Clinical observations implicate longevity factor ⍺Klotho as a key regulator of muscle mass and weakness. Low Klotho levels are reported to correlate with muscle weakness and frailty.Using Klotho null mice, our study shows that Klotho-deficiency promotes skeletal muscle weakness and impaired motor unit connectivity.RNA-sequencing analysis identified altered expression of sarcomeric and synaptic genes suggesting changes to the muscle synapse in Klotho-deficient mice.Histopathological analyses revealed Klotho-deficiency is associated with reduced myofiber caliber, altered muscle composition, and increased prevalence of NCAM+ denervated fibers. Imaging of the NMJ further showed morphological changes and reduced area of synaptic contact.Overall, our findings show that Klotho regulates the structure and function of the NMJ affecting motor unit connectivity which may have an important role in the pathogenesis of muscle wasting and weakness.

DOI: https://doi.org/10.1101/2025.06.11.659129
Bull Exp Biol Med. 2025 Jul 18.

Impairment of P2 Receptor-Mediated Modulation of Skeletal Muscle Contractions in Transgenic Mice with Modeled Amyotrophic Lateral Sclerosis.

A E Khairullin, D V Efimova, A Y Teplov, A N Khabibrakhmanov, K K Nagiev, S N Grishin, A U Ziganshin, M A Mukhamedyarov.

  We studied the effects of ATP on skeletal muscle contractility in FUS-transgenic mice with amyotrophic lateral sclerosis (ALS) model. Mechanomyography showed that ATP application did not increase the amplitude of electrically induced contractions of the diaphragm muscle, m. extensor digitorum longus, and soleus muscle in FUS-transgenic mice unlike wild-type mice. Application of a non-selective P2 receptor antagonist suramine and application of ATP against the background of suramine did not change the amplitude of contractions of the studied skeletal muscles in FUS-transgenic mice. Thus, FUS model of ALS is based on the impairment of purinergic regulation of skeletal muscle contractile activity, which can play a role in the pathogenesis of ALS.

Keywords:  ATP; P2 receptors; amyotrophic lateral sclerosis; neuromuscular synapse; skeletal muscles

DOI:  https://doi.org/10.1007/s10517-025-06425-8
Function (Oxf). 2025 Jul 17. pii: zqaf031. [Epub ahead of print]

Skeletal muscle stem cell mitochondria are transferred to muscle fibers in response to a hypertrophic stimulus.

Jensen Goh, Julia G Williams, Sarah E Ogle, Jai K Joshi, Logan N Scott, Benjamin I Burke, Alex R Keeble, Nicholas T Thomas, Christopher S Fry, Ahmed Ismaeel, John J McCarthy.

  The fusion of skeletal muscle stem cell (MuSC) to myofibers during hypertrophy has exclusively focused on the transfer of the MuSC nucleus, leaving the fate of other MuSC organelles, such as mitochondria, largely unexplored. The objective of this study was to determine if MuSCs transfer their mitochondria upon myofiber fusion in response to a hypertrophic stimulus. To achieve this goal, we specifically labeled MuSC mitochondria with Dendra2 fluorescence by crossing the MuSC-specific CreER (Pax7CreER/CreER) mouse with the Rosa26-Dendra2 mouse to generate the Pax7-Dendra2 mouse. To induce the fusion of MuSC to myofibers, Pax7-Dendra2 mice underwent synergist ablation surgery to induce mechanical overload (MOV) of plantaris muscle for 3, 7 and 14 days. To track MuSC proliferation, a mini-osmotic pump was implanted at the time of MOV to continuously deliver EdU. At the designated time, plantaris muscles were excised and processed for immunohistochemistry to quantify Dendra2 + myofibers. There was a progressive increase in Dendra2-positive fibers across the MOV time course. Three distinct patterns or domains of Dendra2 fluorescence within myofibers were identified and designated as newly fused (NF), crescent (CS) or diffuse (DF). From these Dendra2 + domain types, we inferred MuSC fusion dynamics which indicated MuSC fusion occurred prior to mechanical overload day 3 (MOV-3) and preferentially with Type 2A fibers. Quantification of EdU + myonuclei found the majority of early (MOV < 3 days) MuSC fusion was division-independent, while proliferating MuSCs contributed primarily to later fusion events. The results of this study provide the first evidence that MuSC mitochondria are transferred to myofibers upon fusion during hypertrophy while, unexpectedly, revealing a greater complexity in MuSC fusion than previously recognized.

Keywords:  mitochondrial transfer; muscle stem cell; satellite cell; stem cell dynamics; stem cell fusion

DOI:  https://doi.org/10.1093/function/zqaf031
Acta Neuropathol Commun. 2025 Jul 14. 13(1): 153

Kv3 channel agonist ameliorates the phenotype of a mouse model of amyotrophic lateral sclerosis.

Manuela Marabita, Caterina Marchioretti, Aishwarya Aravamudhan, Simona Zito, Antonella Falconieri, Emanuela Zuccaro, Roberta Andreotti, Lisa Gambarotto, Samuele Metti, Marika Tonellato, Valentina Adami, Kyung Ho Park, Martin J Gunthorpe, Charles H Large, Agostino Marasco, Sara Vianello, Jessica Rosati, Elisa Belluzzi, Assunta Pozzuoli, Carlo Biz, Pietro Ruggieri, Manuela Basso, Angelo Poletti, Giuseppe Alvaro, Gianni Sorarù, Paolo Bonaldo, Ornella Rossetto, Nadia Pilati, Maria Pennuto.

Voltage-gated potassium channels, Kv3.1, Kv3.2, Kv3.3, and Kv3.4, facilitate rapid repolarization and shape action potentials, which are crucial to maintaining high-frequency firing. Little is known about the expression and function of Kv3 channels in skeletal muscle. We show that these channels are expressed in type IIa/IIx fibers, and their transcript levels progressively increase from postnatal age to adulthood in physiological context. In mature myofibers, the Kv3.1 and Kv3.4 channels are enriched in the muscle triads. The expression of the Kv3 channel is lost upon acute motor unit damage, in mouse models of amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), and the skeletal muscle of patients with sporadic ALS. Early treatment of ALS and SBMA mice with AUT00201, a positive allosteric modulator of Kv3 channels, improved the phenotype of ALS mice specifically, suggesting that positive modulation of Kv3 channels is a novel therapeutic option for patients with ALS.

DOI: https://doi.org/10.1186/s40478-025-02067-z
Front Aging. 2025 ;6 1588014

Molecular constraints of sarcopenia in the ageing muscle.

S Damanti, E Senini, R De Lorenzo, A Merolla, S Santoro, C Festorazzi, M Messina, G Vitali, C Sciorati, A A Manfredi, P Rovere-Querini.

  Sarcopenia, the age-related loss of skeletal muscle mass, strength, and function, is driven by a convergence of molecular, cellular, hormonal, nutritional, and neurological alterations. Skeletal muscle comprises multinucleated fibers supported by satellite cells-muscle stem cells essential for repair and regeneration. With age, both the structure and function of these components deteriorate: myonuclei become disorganized, gene expression skews toward catabolic, inflammatory, and fibrotic pathways, and satellite cell numbers and activity decline. Concurrently, mitochondrial dysfunction, impaired proteostasis, and vascular rarefaction limit energy availability and regenerative capacity. Neurodegeneration and age-related muscle fibers denervation further exacerbate muscle loss, particularly affecting fast-twitch fibers, and reduce motor unit integrity. These neural deficits, alongside changes at the neuromuscular junction, contribute to functional decline and diminished contractility. Hormonal changes-including reduced levels of growth hormone, testosterone, and IGF-1-undermine anabolic signaling and promote muscle atrophy. Nutritional factors are also pivotal: anorexia of aging and reduced dietary protein intake lead to suboptimal nutrient availability. Compounding this is anabolic resistance, a hallmark of aging muscle, in which higher levels of dietary protein and amino acids are required to stimulate muscle protein synthesis effectively. Physical inactivity and immobility, often secondary to chronic illness or frailty, further accelerate sarcopenia by promoting disuse atrophy. The molecular constraints of sarcopenia are deeply intertwined with non-molecular mechanisms-such as neuromuscular degeneration, hormonal shifts, inadequate nutrition, and reduced physical activity-creating a complex and self-reinforcing cycle that impairs muscle maintenance and regeneration in the elderly. This review synthesizes current evidence on these interconnected factors, highlighting opportunities for targeted interventions to preserve muscle health across the lifespan.

Keywords:  ageing; constraints; molecular mechainsm; muscle; sarcopenia

DOI:  https://doi.org/10.3389/fragi.2025.1588014
Am J Med Genet B Neuropsychiatr Genet. 2025 Jul 17. e33048

m6A Methylation-Induced Autophagy Impairment by TFEB Regulation in SOD1-G93A ALS Cell Model.

Di An, Yuhao Wu, Jingzhe Han, Pingping Fang, Yi Bu, Guang Ji, Jinliang Deng, Xueqin Song.

  We investigate the role of m6A RNA methylation in regulating transcription factor EB (TFEB) and its contribution to mitochondrial autophagy (mitophagy) dysfunction in amyotrophic lateral sclerosis (ALS). ALS cell models were used to analyse mitophagy markers and TFEB expression under METTL3 and TFEB modulation, using RT-qPCR, Western blot, MeRIP, RIP, and immunofluorescence. Elevated m6A methylation and reduced TFEB expression were observed in hSOD1-G93A models. METTL3 overexpression suppressed TFEB expression, leading to impaired mitophagy, while METTL3 knockdown alleviated these effects. MeRIP assays confirmed increased m6A modifications on TFEB mRNA, and RIP assays demonstrated direct interaction between METTL3 and TFEB mRNA. Notably, TFEB overexpression rescued mitophagy dysfunction, whereas TFEB knockdown exacerbated the impairment. METTL3-mediated m6A methylation inhibits mitophagy by downregulating TFEB expression, revealing the m6A-TFEB pathway as a promising therapeutic target for ALS.

Keywords:  METTL3; amyotrophic lateral sclerosis; m6A methylation; mitochondrial autophagy; transcription factor EB (TFEB)

DOI:  https://doi.org/10.1002/ajmg.b.33048
JCSM Commun. 2025 Jan-Jun;8(1):pii: e117. [Epub ahead of print]8(1):

Intramuscular CMT-167 Tumors Produce a Mild Cachexia Phenotype in C57BL/6J Mice.

Bryan C Remaily, Trang T Vu, Justin Thomas, Kyeongmin Kim, Camille Stanton, Zhiliang Xie, Lauren Granchie, Millennium Manna, Paul Gregorevic, Xiaokui Mo, Jeovanna Lowe, Jill A Rafael-Fortney, Samuel K Kulp, Latha P Ganesan, Dwight H Owen, Thomas A Mace, Christopher C Coss, Mitch A Phelps.

   Background: Cancer cachexia is a debilitating syndrome characterized by irreversible losses in skeletal muscle mass, with or without losses in adipose tissue. Cancer cachexia is an underrecognized syndrome that impacts ~50% of all cancer patients and accounts for up to ~20% of all cancer deaths [1, 2]. Lung cancer remains one of the deadliest cancers in the United States with an estimated 137,000 deaths in the year 2021 alone [3]. Lung cancer is highly comorbid with cancer cachexia [4]. Pre-clinical models are heavily relied upon to study both lung cancer and cancer cachexia, however there is a need to develop novel models to study the relationship between the two diseases. We therefore characterized the cachexia phenotype in the CMT-167 syngeneic lung cancer model.
Methods: Male C57BL6/J mice, aged 8-10 weeks, were administered an intramuscular (IM) injection of either 0.5x106 CMT-167 cells or vehicle. Clinically relevant features of cancer cachexia were assessed 23 days after CMT-167 cell administration in tumor bearing mice by assessment of terminal skeletal muscle and adipose tissue mass, gastrocnemius myofiber cross sectional area (CSA), circulating biomarkers of cachexia, and skeletal muscle E3 ubiquitin ligase mRNA. A single intravenous dose pharmacokinetic study of pembrolizumab was completed to assess tumor status influence upon antibody pharmacokinetics.
Results: Compared to tumor free (TF) mice, we observed lower terminal tumor-adjusted bodyweight, adipose tissue mass, gastrocnemius mass, quadriceps mass, and gastrocnemius myofiber CSA. CMT-167 tumor bearing (TB) mice did not lose bodyweight relative to starting weight, but instead failed to gain as much weight as TF controls. CMT-167 TB mice exhibited increased concentrations of circulating markers of cachexia and muscle wasting, such as IL-6 and TNF-α, although there was no difference in transcription of E3 ubiquitin ligases Trim63 (MuRF-1) and Fbxo32 (atrogin-1) in skeletal muscle compared to TF mice. CMT-167 TB mice exhibited increased catabolic clearance (CL) of the human IgG4 anti-PD-1, pembrolizumab, agreeing with published literature showing increased CL of immune checkpoint inhibitors in cachectic populations [5, 6]. Comparing the IM CMT-167 model to historical data with the well-established IM Lewis Lung Carcinoma model, CMT-167 TB mice displayed a less severe cachectic phenotype in terms of bodyweight and skeletal muscle effects.
Conclusion: The IM CMT-167 model is a syngeneic lung cancer model of mild cachexia. CMT-167 TB mouse is a novel model in which to study cancer cachexia induction, skeletal muscle atrophy, and immune checkpoint inhibitor clearance mechanisms in the context of lung cancer.

Keywords:  Antibody therapies; Cancer Cachexia; Lung Cancer; Muscle Atrophy; Pharmacokinetics

DOI:  https://doi.org/10.1002/rco2.117
Genome Res. 2025 Jul 17. pii: gr.279501.124. [Epub ahead of print]

Transcriptional modulation unique to vulnerable motor neurons predicts ALS across species and SOD1 mutations.

Irene Mei, Susanne Nichterwitz, Melanie Leboeuf, Jik Nijssen, Isadora Lenoel, Dirk Repsilber, Christian S Lobsiger, Eva Hedlund.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons (MNs) that innervate skeletal muscles. However, certain MN groups including ocular MNs, are relatively resilient. To reveal key drivers of resilience versus vulnerability in ALS, we investigate the transcriptional dynamics of four distinct MN populations in SOD1G93A ALS mice using LCM-seq and single molecule fluorescent in situ hybridization. We find that resilient ocular MNs regulate few genes in response to disease. Instead, they exhibit high baseline gene expression of neuroprotective factors including En1, Pvalb, Cd63 and Gal, some of which vulnerable MNs upregulate during disease. Vulnerable motor neuron groups upregulate both detrimental and regenerative responses to ALS and share pathway activation, indicating that breakdown occurs through similar mechanisms across vulnerable neurons, albeit with distinct timing. Meta-analysis across four rodent mutant SOD1 MN transcriptome datasets identify a shared vulnerability code of 39 genes including Atf4, Nupr1, Ddit3, and Penk, involved in apoptosis as well as proregenerative and anti-apoptotic signature consisting of Atf3, Vgf, Ina, Sprr1a, Fgf21, Gap43, Adcyap1, and Mt1 Machine learning using genes upregulated in SOD1G93A spinal MN predicts disease in human stem cell-derived SOD1E100G MNs, and shows that dysregulation of VGF, INA, and PENK are strong disease-predictors across species and SOD1 mutations. Our study reveals MN population-specific gene expression and temporal disease-induced regulation that together provide a basis to explain ALS selective vulnerability and resilience and that can be used to predict disease.

DOI: https://doi.org/10.1101/gr.279501.124
bioRxiv. 2025 Jul 14. pii: 2025.06.22.660773. [Epub ahead of print]

TDP-43 pathology induces CD8+ T cell activation through cryptic epitope recognition.

Shahab Chizari, Matteo Zanovello, Steven Kong, Vidur Saigal, Anna-Leigh Brown, Valentina Turchetti, Luca Zampedri, Iwona Skorupinska, Giacomo Maria Minicuci, Francesca Paron, Paola Tonin, Giulia Marchetto, Ziyi Li, Jennifer Colon-Mercado, Dario Dattilo, Simone Barattucci, Ariana Gatt, Yue Qi, Michael Hanna, Michael Ward, Leonard Petrucelli, Maurizio Romano, Gaetano Vattemi, Emanuele Buratti, Andrea Malaspina, Ashirwad Merve, Pedro Machado, Gianni Soraru, Pietro Fratta, Ning Jiang.

Aggregation and nuclear depletion of the RNA binding protein TDP-43 are the crucial pathological features of amyotrophic lateral sclerosis (ALS) and inclusion body myositis (IBM), two degenerative diseases of the CNS and muscle. The loss of TDP-43 nuclear function results in the aberrant inclusion of cryptic exons in mRNA transcripts, leading to the expression of de novo proteins. Clonally expanded and highly differentiated CD8+ T cells have been observed in individuals with TDP-43 proteinopathies and therapeutics modulating the T cell response have recently been found to extend survival. However, the target antigens mediating T cell activation have remained elusive. Here, we investigate whether the de novo proteins induced by aberrant cryptic splicing due to TDP-43 nuclear loss can act as neo-antigens. We detect the HDGFL2 cryptic peptide and multiple other TDP-43 cryptic exons in IBM skeletal muscle, where their presence correlates with enrichment of T cells and class I antigen presentation pathways. Furthermore, we identify epitopes deriving from HDGFL2 and IGLON5 cryptic peptides which are recognized by clonally expanded and functionally differentiated populations of CD8+ T cells in ALS and IBM Patients. Finally, we demonstrate that T cells engineered to express the identified TCRs can bind and activate in response to the cryptic peptide derived epitopes (cryptic epitopes) and are able to kill TDP-43 deficient astrocytes. This work identifies for the first time specific T cell antigens in ALS and IBM, directly linking adaptive immune response to TDP-43 pathology.

DOI: https://doi.org/10.1101/2025.06.22.660773
iScience. 2025 Jul 18. 28(7): 112880

Targeting phospholipase PLAG-15 promotes healthy aging in C. elegans via lysosomal-related genes.

Sanne van der Rijt, Marte Molenaars, Rashmi Kamble, Weisha Li, Bauke V Schomakers, Adrie D Dane, Simone W Denis, Michel van Weeghel, Frédéric M Vaz, Alessandra Tammaro, Georges E Janssens, Arwen W Gao, Riekelt H Houtkooper.

  Complex lipid metabolism plays a crucial role in regulating aging. We recently discovered that the phospholipid bis(monoacylglycero)phosphate (BMP) increases in aged human muscles and many mouse tissues. The phospholipase PLA2G15 is reportedly involved in BMP synthesis, however, its specific role in aging remains unknown. To elucidate the role of PLA2G15 in aging, we used Caenorhabditis elegans as a model. When silencing plag-15, the predicted worm orthologue of PLA2G15, we observed improved healthspan and lifespan extension. Semi-targeted lipidomics highlighted that instead of changes related to BMP, plag-15 RNAi led to lower levels of lysophosphatidic acid, lysophosphatidylcholine, and lysophosphatidylethanolamine. Transcriptome-guided epistasis experiments identified that the lifespan extension of plag-15 RNAi worms is regulated by transcription factors hlh-30 and elt-3, and lysosomal vitamin B12 transporter pmp-5 (human TFEB, GATA, and ABCD4 respectively). Overall, we conclude that targeting phospholipid remodeling through plag-15 could be a promising strategy to promote healthy aging.

Keywords:  Lipidomics; Molecular physiology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2025.112880
PLoS One. 2025 ;20(7): e0328485

Cellular repressor of E1A-stimulated genes 1 enhances skeletal muscle performance through the stimulation of muscle differentiation and Akt-mTOR signaling pathway activation.

Ayumi Goto, Michihiro Hashimoto, Sho Yokogawa, Yuzu Naruse, Hitoshi Yamashita.

Cellular repressor of E1A-stimulated genes 1 (CREG1), a glycoprotein secreted by various cell types, plays a crucial role in cellular differentiation and energy metabolism. While previous research has linked CREG1 deficiency in skeletal muscles to impaired exercise capacity and altered muscle fiber-type composition, its specific role in skeletal muscle function and differentiation remains unclear. In this study, we investigated the impact of CREG1 on muscle performance and fiber-type composition in adipocyte P2-CREG1-transgenic (Tg) mice and explored muscle differentiation in C2C12 myotubes. Tg mice exhibited significantly improved muscle performance compared to wild-type mice, as indicated by enhanced grip strength. Additionally, the proportion of type IIx fiber in the soleus muscle was significantly increased in Tg mice, along with a tendency towards elevated Myh1 mRNA expression. Enhanced CREG1 expression and activation of the Akt-mTOR signaling pathway, which is involved in muscle protein synthesis, were observed in the skeletal muscles of Tg mice. In C2C12 myotubes, Creg1 knockdown appears to decrease myoblast determination protein 1 (Myod1) expression, while recombinant CREG1 treatment restored Myod1 expression and promoted Akt-mTOR phosphorylation. These findings suggest that CREG1 stimulates muscle differentiation by enhancing protein synthesis, thereby influencing skeletal muscle function.

DOI: https://doi.org/10.1371/journal.pone.0328485
J Anesth. 2025 Jul 17.

Impact of the ICU admission of patients with COVID-19 on the outcomes of patients without COVID-19 in the ICU: a retrospective cohort study.

Chikashi Takeda, Masaaki Sakuraya, Sachiko Tanaka-Mizuno, Kotaro Sakurai, Shinichi Kai, Toshiyuki Mizota, Moritoki Egi.

   PURPOSE: This study aimed to elucidate how the admission of patients with coronavirus disease-2019 (COVID-19) to the intensive care unit (ICU) impacts the mortality rate and management of patients without COVID-19 in the ICU, focusing on the condition of patients during and after ICU admission, which has not been sufficiently evaluated.
METHODS: This multicenter retrospective cohort study was conducted across 33 ICU facilities in Japan, using data from the Japanese Intensive Care Patient Database for fiscal years 2018-2020. Patients without COVID-19 were admitted to ICUs that also treated patients with COVID-19 during the study period. Of the 68,620 patients without COVID-19, 11,503 were admitted during the COVID-19 period. The primary outcome was in-hospital mortality. The secondary outcomes included ICU mortality, off-hour ICU discharge, ICU discharge with mechanical ventilation, and incidence of tracheotomy.
RESULTS: Adjusted analyses revealed no significant difference in in-hospital mortality (adjusted odds ratio [aOR] = 0.90; p = 0.071) but lower ICU mortality (aOR = 0.75; p = 0.001) during the COVID-19 period. The COVID-19 period was associated with increased off-hour ICU discharges (aOR = 1.37; p < 0.001), higher tracheotomy rates (aOR = 1.45; p = 0.018), and increased ICU discharges requiring mechanical ventilation (aOR = 1.21; p = 0.006). Moreover, ICU bed occupancy rates were lower in patients without COVID-19.
CONCLUSION: In-hospital mortality in patients without COVID-19 during the COVID-19 period was not significantly different from that during the non-COVID-19 period. While ICU mortality decreased, the tracheostomy rate, rate of patients requiring ventilators at the time of ICU discharge, and rate of transfer to other facilities increased.

Keywords:  Bed occupancy; COVID-19 pandemic; Intensive care unit; Mortality; Patient discharge

DOI:  https://doi.org/10.1007/s00540-025-03549-z
Life Sci. 2025 Jul 12. pii: S0024-3205(25)00489-8. [Epub ahead of print] 123854

Mitochondrial p32-mediated regulation of p-TBK1 affects the radiosensitivity of colorectal cancer.

Yanjin Wu, Haitao Zhou, Jiahui Meng, Wenyue Zhao, Xiaotong Zhao, Yujia Hou, Qin Wang, Feng Wang, Qiang Liu, Yang Liu.

   PURPOSE: Many colorectal cancer (CRC) patients respond poorly to radiotherapy due to radioresistance. Understanding the molecular mechanisms underlying this resistance is crucial. It was demonstrated that p32, a mitochondrial protein translation regulator, is related to cancer development. However, its specific function and mechanism in CRC, has not yet been investigated. This study aims to explore the role of p32 in CRC and its impact on radiotherapy sensitivity.
METHODS: Cell viability was evaluated by MTT and EdU assay. Mitochondrial DNA (mtDNA) leakage was quantified by RT-qPCR. Radiosensitivity was indicated by cellular phosphorylation of H2AX (γH2AX) foci, phosphorylation of ataxia telangiectasia mutated (p-ATM) and phosphorylation of checkpoint kinase 2 (p-CHK2) levels, as well as by mice tumor model subjected to radiotherapy. Moreover, histological and transcriptomic analysis of p32 expression were performed in CRC patients.
RESULTS: In p32-KO cells, we observed reduced cell viability, damaged mitochondria, mtDNA leakage, and increased radiosensitivity. Furthermore, depletion of p32 induced the DNA damage response (DDR) by activating cytoplasmic DNA sensing cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-TANK-binding kinase 1 (TBK1), which was reversed by p32/TBK1 double knockout. Depletion of p32 also induced the mitochondrial fragmentation, induced mtDNA leakage through the mitochondrial permeability transition pore (mPTP), effects that could be mitigated by Mdivi-1 or Cyclosporin A (CsA).
CONCLUSIONS: Our study demonstrates that inhibiting p32 in CRC enhances radiosensitivity by causing mitochondrial dysfunction, increasing mitochondrial fission, inducing mtDNA leakage and activating the cGAS-STING-TBK1 pathway. These findings provide a potential therapeutic target for overcoming radioresistance in CRC.

Keywords:  Mitochondria dysfunction; Radiosensitivity; cGAS-STING-TBK1; mPTP; mtDNA

DOI:  https://doi.org/10.1016/j.lfs.2025.123854
JCI Insight. 2025 Jul 15. pii: e192047. [Epub ahead of print]

Inhibition of AhR improves cortical bone and skeletal muscle function via preservation of neuromuscular junctions.

Kanglun Yu, Sagar Vyavahare, Dima W Alhamad, Husam Bensreti, Ling Ruan, Anik Tuladhar, Caihong Dai, Joseph C Shaver, Alok Tripathi, Kehong Ding, Rafal Pacholczyk, Marion A Cooley, Roger Zhong, Maribeth H Johnson, Jie Chen, Wendy B Bollag, Carlos M Isales, William D Hill, Mark W Hamrick, Sadanand Fulzele, Meghan E McGee-Lawrence.

  The aryl hydrocarbon receptor (AhR) is proposed to mediate the frailty-promoting effects of the tryptophan metabolite kynurenine (Kyn), which increases with age in mice and humans. The goal of the current study was to test whether administration of pharmacological AhR inhibitors, BAY2416964 and CH-223191, could abrogate musculoskeletal decline in aging mice. Female C57BL/6 mice (18 months old) were treated with vehicle (VEH) or BAY2416964 (30 mg/kg) via daily oral gavage 5 days/week for 8 weeks. A second AhR antagonist, CH-223191, was administered to 16-month-old male and female C57BL/6 mice via intraperitoneal injections (3.3 mg/kg) 3 days/week for 12 weeks. While grip strength declined over time in VEH-treated mice, BAY2416964 preserved grip strength in part by improving integrity of neuromuscular junctions, an effect replicated during in vitro studies with siRNA against AhR. Cortical bone mass was also greater in BAY2416964- than VEH-treated mice. Similarly, CH-223191 treatment improved cortical bone and showed beneficial effects in skeletal muscle, including reducing oxidative stress as compared to VEH-treated animals. Transcriptomic and proteomic data from BAY2416964-treated mice supported a positive impact of BAY2416964 on molecular targets that affect neuromuscular junction function. Taken together, these data support AhR as a therapeutic target for improving musculoskeletal health during aging.

Keywords:  Aging; Bone biology; Osteoclast/osteoblast biology; Osteoporosis; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.192047