bims-musmir 2024-10-13 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024‒10‒13
fourteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Alternative splicing dysregulation across tissue and therapeutic approaches in a mouse model of myotonic dystrophy type 1.
Differential evaluation of neuromuscular injuries to understand re-innervation at the neuromuscular junction.
DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.
Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes.
A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore.
A partial loss-of-function variant (Ile191Val) of the TAS1R2 glucose receptor is associated with enhanced responses to exercise training in older adults with obesity: A translational study.
Lysosomal LRRC8 complex regulates lysosomal pH, morphology and systemic glucose metabolism.
Fundamental Body Composition Principles Provide Context for Fat-Free and Skeletal Muscle Loss With GLP-1 RA Treatments.
Mechanisms of the NAD+ salvage pathway in enhancing skeletal muscle function.
Spatial multi-omics in whole skeletal muscle reveals complex tissue architecture.
Sex-specific role of RNA-binding protein, pAUF1, on prolonged hypersensitivity after repetitive ischemia with reperfusion injury.
Spatial analysis of transcript and protein levels in skeletal muscle.
Elevated serum mtDNA in COVID-19 patients is linked to SARS-CoV-2 envelope protein targeting mitochondrial VDAC1, inducing apoptosis and mtDNA release.
Sorafenib induces cachexia by impeding transcriptional signaling of the SET1/MLL complex on muscle-specific genes.

Mol Ther Nucleic Acids. 2024 Dec 10. 35(4): 102338

Alternative splicing dysregulation across tissue and therapeutic approaches in a mouse model of myotonic dystrophy type 1.

Sawyer M Hicks, Jesus A Frias, Subodh K Mishra, Marina Scotti, Derek R Muscato, M Carmen Valero, Leanne M Adams, John D Cleary, Masayuki Nakamori, Eric Wang, J Andrew Berglund.

  Myotonic dystrophy type 1 (DM1), the leading cause of adult-onset muscular dystrophy, is caused by a CTG repeat expansion. Expression of the repeat causes widespread alternative splicing (AS) defects and downstream pathogenesis, including significant skeletal muscle impacts. The HSA LR mouse model plays a significant role in therapeutic development. This mouse model features a transgene composed of approximately 220 interrupted CTG repeats, which results in skeletal muscle pathology that mirrors DM1. To better understand this model and the growing number of therapeutic approaches developed with it, we performed a meta-analysis of publicly available RNA sequencing data for AS changes across three widely examined skeletal muscles: quadriceps, gastrocnemius, and tibialis anterior. Our analysis demonstrated that transgene expression correlated with the extent of splicing dysregulation across these muscles from gastrocnemius (highest), quadriceps (medium), to tibialis anterior (lowest). We identified 95 splicing events consistently dysregulated across all examined datasets. Comparison of splicing rescue across seven therapeutic approaches showed a range of rescue across the 95 splicing events from the three muscle groups. This analysis contributes to our understanding of the HSA LR model and the growing number of therapeutic approaches currently in preclinical development for DM1.

Keywords:  DM1; HSALR; MT: Bioinformatics; RNA sequencing; RNA-seq; alternative splicing; therapeutics

DOI:  https://doi.org/10.1016/j.omtn.2024.102338
Exp Neurol. 2024 Oct 09. pii: S0014-4886(24)00322-4. [Epub ahead of print] 114996

Differential evaluation of neuromuscular injuries to understand re-innervation at the neuromuscular junction.

Daniel B Hoffman, Christiana J Raymond-Pope, Emma E Pritchard, Angela S Bruzina, Thomas J Lillquist, Benjamin T Corona, Jarrod A Call, Sarah M Greising.

  Peripheral nerve-crush injury is a well-established model of neuromuscular junction (NMJ) denervation and subsequent re-innervation. Functionally, the skeletal muscle follows a similar pattern as neural recovery, with immediate loss of force production that steadily improves in parallel with rates of re-innervation. On the other hand, traumatic injury to the muscle itself, specifically volumetric muscle loss (VML), results in an irrecoverable loss of muscle function. Recent work has indicated significant impairments to the NMJ following this injury that appear chronic in nature, alongside the lack of functional recovery. Thus, the goal of this study was to compare the effects of nerve and muscle injury on NMJ remodeling. Even numbers of adult male and female mice were used with three experimental groups: injury Naïve, nerve crush, and VML injury; and three terminal timepoints: 3-, 48-, and 112-days post-injury. Confirming the assumed recoverability of the two injury models, we found in vivo maximal torque was fully restored following nerve-crush injury but remained at a significant deficit following VML. Compared to injury Naïve and nerve-crush injury, we found VML results in aberrantly high trophic signaling (e.g., neuregulin-1) and numbers of supporting cells, including terminal Schwann cells and sub-synaptic nuclei. In some cases, sex differences were detected, including higher rates of innervation in females than males. Both nerve crush and VML injury display chronic changes to NMJ morphology, such as increased fragmentation and nerve sprouting, highlighting the potential of VML for modeling NMJ regeneration in adulthood, alongside the established nerve-injury models.

Keywords:  Denervation; Neurotrophic factors; Sub-synaptic nuclei; Terminal Schwann cells; Volumetric muscle loss

DOI:  https://doi.org/10.1016/j.expneurol.2024.114996
EMBO J. 2024 Oct 08.

DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.

Hsin-Pin Lin, Jennifer D Petersen, Alexandra J Gilsrud, Angelo Madruga, Theresa M D'Silva, Xiaoping Huang, Mario K Shammas, Nicholas P Randolph, Kory R Johnson, Yan Li, Drew R Jones, Michael E Pacold, Derek P Narendra.

  Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.

Keywords:  Mitochondria Unfolded Protein Response (mt-UPR); Mitochondrial Disorders; Mitohormesis; Mitonuclear Communication; Mitophagy

DOI:  https://doi.org/10.1038/s44318-024-00242-x
Sci Transl Med. 2024 Oct 09. 16(768): eado3022

Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes.

David Rizo-Roca, Dimitrius Santiago P S F Guimarães, Logan A Pendergrast, Nicolas Di Leo, Alexander V Chibalin, Salwan Maqdasy, Mikael Rydén, Erik Näslund, Juleen R Zierath, Anna Krook.

Increased plasma creatine concentrations are associated with the risk of type 2 diabetes, but whether this alteration is associated with or causal for impairments in metabolism remains unexplored. Because skeletal muscle is the main disposal site of both creatine and glucose, we investigated the role of intramuscular creatine metabolism in the pathophysiology of insulin resistance in type 2 diabetes. In men with type 2 diabetes, plasma creatine concentrations were increased, and intramuscular phosphocreatine content was reduced. These alterations were coupled to reduced expression of sarcomeric mitochondrial creatine kinase 2 (CKMT2). In C57BL/6 mice fed a high-fat diet, neither supplementation with creatine for 2 weeks nor treatment with the creatine analog β-GPA for 1 week induced changes in glucose tolerance, suggesting that increased circulating creatine was associated with insulin resistance rather than causing it. In C2C12 myotubes, silencing Ckmt2 using small interfering RNA reduced mitochondrial respiration, membrane potential, and glucose oxidation. Electroporation-mediated overexpression of Ckmt2 in skeletal muscle of high-fat diet-fed male mice increased mitochondrial respiration, independent of creatine availability. Given that overexpression of Ckmt2 improved mitochondrial function, we explored whether exercise regulates CKMT2 expression. Analysis of public data revealed that CKMT2 content was up-regulated by exercise training in both humans and mice. We reveal a previously underappreciated role of CKMT2 in mitochondrial homeostasis beyond its function for creatine phosphorylation, independent of insulin action. Collectively, our data provide functional evidence for how CKMT2 mediates mitochondrial dysfunction associated with type 2 diabetes.

DOI: https://doi.org/10.1126/scitranslmed.ado3022
Acta Neuropathol Commun. 2024 Oct 10. 12(1): 161

A pathogenic mutation in the ALS/FTD gene VCP induces mitochondrial hypermetabolism by modulating the permeability transition pore.

Silke Vanderhaeghe, Jovan Prerad, Arun Kumar Tharkeshwar, Elien Goethals, Katlijn Vints, Jimmy Beckers, Wendy Scheveneels, Eveline Debroux, Katrien Princen, Philip Van Damme, Marc Fivaz, Gerard Griffioen, Ludo Van Den Bosch.

  Valosin-containing protein (VCP) is a ubiquitously expressed type II AAA+ ATPase protein, implicated in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This study aimed to explore the impact of the disease-causing VCPR191Q/wt mutation on mitochondrial function using a CRISPR/Cas9-engineered neuroblastoma cell line. Mitochondria in these cells are enlarged, with a depolarized mitochondrial membrane potential associated with increased respiration and electron transport chain activity. Our results indicate that mitochondrial hypermetabolism could be caused, at least partially, by increased calcium-induced opening of the permeability transition pore (mPTP), leading to mild mitochondrial uncoupling. In conclusion, our findings reveal a central role of the ALS/FTD gene VCP in maintaining mitochondrial homeostasis and suggest a model of pathogenesis based on progressive alterations in mPTP physiology and mitochondrial energetics.

Keywords:  Amyotrophic lateral sclerosis; Frontotemporal dementia; Mitochondria; Mitochondrial dysfunction; Mitochondrial permeability transition pore; VCP

DOI:  https://doi.org/10.1186/s40478-024-01866-0
Metabolism. 2024 Oct 09. pii: S0026-0495(24)00273-7. [Epub ahead of print] 156045

A partial loss-of-function variant (Ile191Val) of the TAS1R2 glucose receptor is associated with enhanced responses to exercise training in older adults with obesity: A translational study.

Joan Serrano, Saki Kondo, Grace M Link, Ian S Brown, Richard E Pratley, Kedryn K Baskin, Bret H Goodpaster, Paul M Coen, George A Kyriazis.

  BACKGROUND: The TAS1R2 receptor, known for its role in taste perception, has also emerged as a key regulator of muscle physiology. Previous studies have shown that genetic ablation of TAS1R2 in mice enhances muscle fitness mimicking responses to endurance exercise training. However, the translational relevance of these findings to humans remains uncertain.METHODS: We explored responses to endurance exercise training in mice and humans with genetic deficiency of TAS1R2. First, we assessed the effects of muscle-specific deletion of TAS1R2 in mice (mKO) or wild type controls (mWT) following 4 weeks of voluntary wheel running (VWR). Next, we investigated the effects of the TAS1R2-Ile191Val (rs35874116) partial loss-of-function variant on responses to a 6-month diet-induced weight loss with exercise training (WLEX), weight loss alone (WL), or education control (CON) interventions in older individuals with obesity. Participants were retrospectively genotyped for the TAS1R2-Ile191Val polymorphism and classified as conventional function (Ile/Ile) or partial loss-of-function (Val carriers: Ile/Val and Val/Val). Body composition, cardiorespiratory fitness, and skeletal muscle mitochondrial function were assessed before and after the intervention.
RESULTS: In response to VWR, mKO mice demonstrated enhanced running endurance and mitochondrial protein content. Similarly, TAS1R2 Val carriers exhibited distinctive improvements in body composition, including increased muscle mass, along with enhanced cardiorespiratory fitness and mitochondrial function in skeletal muscle following the WLEX intervention compared to Ile/Ile counterparts. Notably, every Val carrier demonstrated substantial responses to exercise training and weight loss, surpassing all Ile/Ile participants in overall performance metrics.
CONCLUSIONS: Our findings suggest that TAS1R2 partial loss-of-function confers beneficial effects on muscle function and metabolism in humans in response to exercise training, akin to observations in TAS1R2 muscle-deficient mice. Targeting TAS1R2 may help enhancing exercise training adaptations in individuals with compromised exercise tolerance or metabolic disorders, presenting a potential avenue for personalized exercise interventions.

Keywords:  Aging; Exercise; Genetics; HbA1c; Mitochondria; Muscle mass; Muscle metabolism; NAD; Obesity; PDE; Polymorphism; Running; Sweet taste receptor; TAS1R2; Weight loss; rs35874116

DOI:  https://doi.org/10.1016/j.metabol.2024.156045
bioRxiv. 2024 Sep 23. pii: 2024.09.22.614256. [Epub ahead of print]

Lysosomal LRRC8 complex regulates lysosomal pH, morphology and systemic glucose metabolism.

Ashutosh Kumar, Yonghui Zhao, Litao Xie, Rahul Chadda, Nihil Abraham, Juan Hong, Ethan Feng, John D Tranter, David Rawnsley, Haiyan Liu, Kyla M Henry, Gretchen Meyer, Meiqin Hu, Haoxing Xu, Antentor Hinton, Chad E Grueter, E Dale Abel, Andrew W Norris, Abhinav Diwan, Rajan Sah.

The lysosome integrates anabolic signalling and nutrient-sensing to regulate intracellular growth pathways. The leucine-rich repeat containing 8 (LRRC8) channel complex forms a lysosomal anion channel and regulates PI3K-AKT-mTOR signalling, skeletal muscle differentiation, growth, and systemic glucose metabolism. Here, we define the endogenous LRRC8 subunits localized to a subset of lysosomes in differentiated myotubes. We show LRRC8A regulates leucine-stimulated mTOR, lysosome size, number, pH, and expression of lysosomal proteins LAMP2, P62, LC3B, suggesting impaired autophagic flux. Mutating a LRRC8A lysosomal targeting dileucine motif sequence (LRRC8A-L706A;L707A) in myotubes recapitulates the abnormal AKT signalling and altered lysosomal morphology and pH observed in LRRC8A KO cells. In vivo , LRRC8A-L706A;L707A KI mice exhibit increased adiposity, impaired glucose tolerance and insulin resistance characterized by reduced skeletal muscle glucose-uptake, and impaired incorporation of glucose into glycogen. These data reveal a lysosomal LRRC8 mediated metabolic signalling function that regulates lysosomal activity, systemic glucose homeostasis and insulin-sensitivity.

DOI: https://doi.org/10.1101/2024.09.22.614256
J Endocr Soc. 2024 Sep 26. 8(11): bvae164

Fundamental Body Composition Principles Provide Context for Fat-Free and Skeletal Muscle Loss With GLP-1 RA Treatments.

Grant M Tinsley, Steven B Heymsfield.

  During weight loss, reductions in body mass are commonly described using molecular body components (eg, fat mass and fat-free mass [FFM]) or tissues and organs (eg, adipose tissue and skeletal muscle). While often conflated, distinctions between body components established by different levels of the 5-level model of body composition-which partitions body mass according to the atomic, molecular, cellular, tissue/organ, or whole-body level-are essential to recall when interpreting the composition of weight loss. A contemporary area of clinical and research interest that demonstrates the importance of these concepts is the discussion surrounding body composition changes with glucagon-like peptide-1 receptor agonists (GLP-1RA), particularly in regard to changes in FFM and skeletal muscle mass. The present article emphasizes the importance of fundamental principles when interpreting body composition changes experienced during weight loss, with a particular focus on GLP-1RA drug trials. The potential for obligatory loss of FFM due to reductions in adipose tissue mass and distribution of FFM loss from distinct body tissues are also discussed. Finally, selected countermeasures to combat loss of FFM and skeletal muscle, namely resistance exercise training and increased protein intake, are presented. Collectively, these considerations may allow for enhanced clarity when conceptualizing, discussing, and seeking to influence body composition changes experienced during weight loss.

Keywords:  exercise; glucagon-like peptide-1 receptor agonist; lean body mass; lean mass; obesity; weight loss

DOI:  https://doi.org/10.1210/jendso/bvae164
Front Cell Dev Biol. 2024 ;12 1464815

Mechanisms of the NAD+ salvage pathway in enhancing skeletal muscle function.

Mengzhu Su, Fanghui Qiu, Yansong Li, Tongtong Che, Ningning Li, Shuangshuang Zhang.

  Nicotinamide adenine dinucleotide (NAD+) is crucial for cellular energy production, serving as a coenzyme in oxidation-reduction reactions. It also supports enzymes involved in processes such as DNA repair, aging, and immune responses. Lower NAD+ levels have been associated with various diseases, highlighting the importance of replenishing NAD+. Nicotinamide phosphoribosyltransferase (NAMPT) plays a critical role in the NAD+ salvage pathway, which helps sustain NAD+ levels, particularly in high-energy tissues like skeletal muscle.This review explores how the NAMPT-driven NAD+ salvage pathway influences skeletal muscle health and functionality in aging, type 2 diabetes mellitus (T2DM), and skeletal muscle injury. The review offers insights into enhancing the salvage pathway through exercise and NAD+ boosters as strategies to improve muscle performance. The findings suggest significant potential for using this pathway in the diagnosis, monitoring, and treatment of skeletal muscle conditions.

Keywords:  NAD+; NAMPT; T2DM; aging; skelelal muscle

DOI:  https://doi.org/10.3389/fcell.2024.1464815
Commun Biol. 2024 Oct 05. 7(1): 1272

Spatial multi-omics in whole skeletal muscle reveals complex tissue architecture.

Clara Martínez Mir, Paola Pisterzi, Isabel De Poorter, Maria Rilou, Melissa van Kranenburg, Bram Heijs, Anna Alemany, Fanny Sage, Niels Geijsen.

Myofibers are large multinucleated cells that have long thought to have a rather simple organization. Single-nucleus transcriptomics, spatial transcriptomics and spatial metabolomics analysis have revealed distinct transcription profiles in myonuclei related to myofiber type. However, the use of local tissue collection or dissociation methods have obscured the spatial organization. To elucidate the full tissue architecture, we combine two spatial omics, RNA tomography and mass spectrometry imaging. This enables us to map the spatial transcriptomic, metabolomic and lipidomic organization of the whole murine tibialis anterior muscle. Our findings on heterogeneity in fiber type proportions are validated with multiplexed immunofluorescence staining in tibialis anterior, extensor digitorum longus and soleus. Our results demonstrate unexpectedly strong regionalization of gene expression, metabolic differences and variable myofiber type proportion along the proximal-distal axis. These new insights in whole-tissue level organization reconcile sometimes conflicting results coming from previous studies relying on local sampling methods.

DOI: https://doi.org/10.1038/s42003-024-06949-1
Pain. 2024 Oct 08.

Sex-specific role of RNA-binding protein, pAUF1, on prolonged hypersensitivity after repetitive ischemia with reperfusion injury.

Meranda M Quijas, Luis F Queme, Samantha T Woodke, Alex A Weyler, Dana Buesing, Ally Butterfield, Diya P Joshi, Irati Mitxelena-Balerdi, Yvonne M Ulrich-Lai, Michael P Jankowski.

ABSTRACT: Repetitive ischemia with reperfusion (I/R) injury is a common cause of myalgia. Ischemia with reperfusion injuries occur in many conditions that differentially affect males and females including complex regional pain syndrome and fibromyalgia. Our preclinical studies have indicated that primary afferent sensitization and behavioral hypersensitivity caused by I/R injury may be due to sex-specific gene expression in the dorsal root ganglia (DRG) and distinct upregulation of growth factors and cytokines in the affected muscles. To determine how these unique gene expression programs may be established in a sex-dependent manner in a model that more closely mimics clinical scenarios, we used a developed prolonged ischemic myalgia model in mice whereby animals experience repeated I/R injuries and compared behavioral results with unbiased and targeted screening strategies in male and female DRG. Several distinct proteins were found to be differentially expressed in male and female DRG, including phosphorylated AU-rich element RNA-binding protein (pAUF1), which is known to regulate gene expression. Nerve-specific siRNA-mediated knockdown of AUF1 inhibited prolonged hypersensitivity in females only, whereas overexpression of AUF1 in male DRG neurons increased pain-like responses. AUF1 knockdown was able to specifically inhibit repeated I/R-induced gene expression in females potentially downstream of prolactin receptor signaling. Data suggest RNA-binding proteins such as pAUF1 may underlie the sex-specific effects on DRG gene expression that modulates behavioral hypersensitivity after repeated I/R injury through prolactin signaling. This study may aid in finding distinct receptor differences related to the evolution of acute to chronic ischemic muscle pain development between sexes.

DOI: https://doi.org/10.1097/j.pain.0000000000003415
STAR Protoc. 2024 Oct 09. pii: S2666-1667(24)00543-4. [Epub ahead of print]5(4): 103378

Spatial analysis of transcript and protein levels in skeletal muscle.

Paola Pisterzi, Clara Martinez Mir, Ouafa Dahri, Isabel de Poorter, Sandra Batlles Parera, Milica Dostanić, Massimo Mastrangeli, Christine Mummery, Niels Geijsen, Fanny Sage.

  Skeletal muscle spatial analyses have revealed unexpected regionalized gene expression patterns challenging the understanding of muscle as a homogeneous tissue. Here, we present a protocol for the spatial analysis of transcript and protein levels in murine skeletal muscle. We describe steps for tibialis anterior dissection, formaldehyde fixation, tissue chopper cutting, and hybridization chain reaction (HCR) detection and amplification. We then detail procedures for immunostaining, tissue clearing, and imaging. This protocol is easily adaptable to other tissues.

Keywords:  Gene Expression; In Situ Hybridization; Microscopy; Tissue Engineering

DOI:  https://doi.org/10.1016/j.xpro.2024.103378
Apoptosis. 2024 Oct 07.

Elevated serum mtDNA in COVID-19 patients is linked to SARS-CoV-2 envelope protein targeting mitochondrial VDAC1, inducing apoptosis and mtDNA release.

Anna Shteinfer-Kuzmine, Ankit Verma, Rut Bornshten, Eli Ben Chetrit, Ami Ben-Ya'acov, Hadas Pahima, Ethan Rubin, Yosef Mograbi, Eyal Shteyer, Varda Shoshan-Barmatz.

  Mitochondria dysfunction is implicated in cell death, inflammation, and autoimmunity. During viral infections, some viruses employ different strategies to disrupt mitochondria-dependent apoptosis, while others, including SARS-CoV-2, induce host cell apoptosis to facilitate replication and immune system modulation. Given mitochondrial DNAs (mtDNA) role as a pro-inflammatory damage-associated molecular pattern in inflammatory diseases, we examined its levels in the serum of COVID-19 patients and found it to be high relative to levels in healthy donors. Furthermore, comparison of serum protein profiles between healthy individuals and SARS-CoV-2-infected patients revealed unique bands in the COVID-19 patients. Using mass spectroscopy, we identified over 15 proteins, whose levels in the serum of COVID-19 patients were 4- to 780-fold higher. As mtDNA release from the mitochondria is mediated by the oligomeric form of the mitochondrial-gatekeeper-the voltage-dependent anion-selective channel 1 (VDAC1)-we investigated whether SARS-CoV-2 protein alters VDAC1 expression. Among the three selected SARS-CoV-2 proteins, small envelope (E), nucleocapsid (N), and accessory 3b proteins, the E-protein induced VDAC1 overexpression, VDAC1 oligomerization, cell death, and mtDNA release. Additionally, this protein led to mitochondrial dysfunction, as evidenced by increased mitochondrial ROS production and cytosolic Ca2+ levels. These findings suggest that SARS-CoV-2 E-protein induces mitochondrial dysfunction, apoptosis, and mtDNA release via VDAC1 modulation. mtDNA that accumulates in the blood activates the cGAS-STING pathway, triggering inflammatory cytokine and chemokine expression that contribute to the cytokine storm and tissue damage seen in cases of severe COVID-19.

Keywords:  Apoptosis; COVID-19; Mitochondria; VDAC1; mtDNA

DOI:  https://doi.org/10.1007/s10495-024-02025-5
iScience. 2024 Oct 18. 27(10): 110913

Sorafenib induces cachexia by impeding transcriptional signaling of the SET1/MLL complex on muscle-specific genes.

Bushra Khan, Chiara Lanzuolo, Valentina Rosti, Philina Santarelli, Andreas Pich, Theresia Kraft, Mamta Amrute-Nayak, Arnab Nayak.

  Chemotherapeutics used in cancer therapy are often linked to muscle wasting or cachexia. Insights into the molecular basis of chemotherapy-induced cachexia is essential to improve treatment strategies. Here, we demonstrated that Sorafenib-tyrosine kinase inhibitor (TKI) class of chemotherapeutic agents-induced cachexia. System-wide analyses revealed that Sorafenib alters the global transcriptional program and proteostasis in muscle cells. Mechanistically, Sorafenib treatment reduced active epigenetic mark H3K4 methylation on distinct muscle-specific genes by impeding chromatin association of SET1A-catalytic component of the SET1/MLL histone methyltransferase complex. This mechanism favored transcriptional disorientation that led to disrupted sarcomere assembly, calcium homeostasis and mitochondrial respiration. Consequently, the contractile ability of muscle cells was severely compromised. Interestingly, the other prominent TKIs Nilotinib and Imatinib did not exert similar effects on muscle cell physiology. Collectively, we identified an unanticipated transcriptional mechanism underlying Sorafenib-induced cachexia. Our findings hold the potential to strategize therapy regimens to minimize chemotherapy-induced cachexia.

Keywords:  Health sciences; Internal medicine; Medical specialty; Medicine; Oncology

DOI:  https://doi.org/10.1016/j.isci.2024.110913