bims-musmir 2025-11-09 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–11–09
twelve papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Transcriptional landscape of skeletal muscle in cancer patients.
The mitochondrial-targeted antioxidant SkQ1 prevents skeletal muscle mitochondrial-apoptotic but not necroptotic signalling during ovarian cancer.
Belt-type electrical muscle stimulation preserves muscle fiber size but does not improve muscle function in a rat model of cancer cachexia.
Syntaphilin loss enhances mitochondrial axonal transport and neuromuscular junction formation in a human stem cell derived neuromuscular assembloid model.
Retrospective transcriptomic analysis indicates temporal dysregulation of mitochondrial genes and metabolic pathways after volumetric muscle loss injury.
Transcriptomic analysis of mitohormesis associated with lifespan extension in Caenorhabditis elegans.
Effect of preoperative cancer cachexia on postoperative sarcopenia in patients with non-small cell lung cancer.
NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.
Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.
Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline.
Secretome translation shaped by lysosomes and lunapark-marked ER junctions.
Clinical value and pro-inflammatory mechanism of miR-503-5p as a novel diagnostic biomarker for Sepsis.

Trends Mol Med. 2025 Oct 31. pii: S1471-4914(25)00255-2. [Epub ahead of print]

Transcriptional landscape of skeletal muscle in cancer patients.

Samet Agca, Serkan Kir.

  Bhatt et al. have identified two RNAome-based skeletal muscle subtypes in cancer cachexia. The first subtype is cachexia associated with weight and muscle loss, fiber atrophy, and shortened survival. Furthermore, this subtype has dysregulated post-transcriptional networks involving hub long noncoding (lnc)RNAs, neuronal, immune, and metabolic pathways. The study highlights new biomarkers and network-targeted interventions.

Keywords:  RNAome; cancer cachexia; skeletal muscle

DOI:  https://doi.org/10.1016/j.molmed.2025.10.004
J Physiol. 2025 Nov 02.

The mitochondrial-targeted antioxidant SkQ1 prevents skeletal muscle mitochondrial-apoptotic but not necroptotic signalling during ovarian cancer.

Shahrzad Khajehzadehshoushtar, Luca J Delfinis, Fasih A Rahman, Madison C Garibotti, Shivam Gandhi, Aditya N Brahmbhatt, Brooke A Morris, Bianca Garlisi, Sylvia Lauks, Caroline Aitken, Leslie Ogilvie, Zhu-Xu Zhang, Jeremy A Simpson, Joe Quadrilatero, Jim Petrik, Christopher G R Perry.

  The degree to which mitochondrial-linked programmed cell death pathways contribute to skeletal muscle atrophy during cancer remains unknown. Here we combined a novel and robust mouse model of metastatic ovarian cancer with chronic administration of the mitochondrial-targeted antioxidant SkQ1 to determine the time-dependent and muscle-specific relationships of mitochondrial-linked apoptotic and necroptotic signalling to the development of muscle atrophy in the type IIB-rich gastrocnemius. Early-stage ovarian cancer reduced type IIB fibre cross-sectional area in the gastrocnemius but did not alter mitochondrial H2O2 emission despite increased activities of mitochondrial-linked caspase-9 and -3 regulators of apoptosis. During late-stage ovarian cancer sustained atrophy was associated with increased mitochondrial H2O2 emission potential in vitro, a greater probability of calcium-triggered mitochondrial permeability transition and increases in downstream caspase-9 and -3 activities. SkQ1 attenuated mitochondrial H2O2 emission and caspase-9 and -3 activities in late-stage ovarian cancer but did not prevent atrophy. Necroptosis markers were heterogeneous across time with total RIPK1 increasing during early-stage cancer, which reverted to normal levels by late stages, whereas phosphorylated RIPK3 decreased below control levels. These discoveries indicate that preventing increases in mitochondrial-linked apoptotic caspase-9 and -3 activities during late-stage ovarian cancer with SkQ1 does not prevent atrophy of type II B fibres. Furthermore necroptotic markers are inconclusive during cancer in this muscle type but are not modified by SkQ1. These results do not support a causal relationship between mitochondrial H2O2-linked apoptotic or necroptotic signalling and atrophy in type IIB fibres during ovarian cancer but do not rule out potential relationships in other muscle types. KEY POINTS: Cancer increases mitochondrial reactive oxygen species (ROS) in skeletal muscle during atrophy, but the role of ROS in regulating cell death remains unknown. We show that attenuating gastrocnemius mitochondrial ROS with the mitochondrial-targeted antioxidant SkQ1 prevented mitochondrial-linked pro-apoptotic caspase 9- and -3 activities but did not affect markers of necroptosis in a mouse model of ovarian cancer. Reductions in gastrocnemius muscle fibre cross-sectional areas and the wet weights of several muscles were not prevented by SkQ1. These findings demonstrate that mitochondrial ROS regulate apoptotic caspases but not necroptotic proteins, and neither pathway is linked to gastrocnemius atrophy in mice with ovarian cancer. The degree to which mitochondrial ROS-linked cell death pathways regulate muscle mass in other muscle types and cancer models requires further investigation.

Keywords:  apoptosis; cachexia; mitochondria; necroptosis; ovarian cancer; skeletal muscle

DOI:  https://doi.org/10.1113/JP287912
PLoS One. 2025 ;20(11): e0336391

Belt-type electrical muscle stimulation preserves muscle fiber size but does not improve muscle function in a rat model of cancer cachexia.

Karina Kouzaki, Mako Isemura, Yuki Tamura, Hiroyuki Uno, Shunta Tadano, Ryuji Akimoto, Katsu Hosoki, Koichi Nakazato.

Cancer cachexia causes severe muscle wasting, and current treatments remain limited. Belt-type electrical muscle stimulation (bEMS) has emerged as a passive rehabilitation tool capable of activating multiple lower limb muscles simultaneously. We investigated whether bEMS prevents muscle wasting and improves functional outcomes in rats with cancer cachexia. Cancer cachexia was induced in male Sprague-Dawley rats by intraperitoneal injection of AH130 Yoshida hepatoma cells. Acute and chronic effects of bEMS were tested. Muscle protein synthesis was evaluated using the SUnSET method, and muscle fiber cross-sectional area (CSA) and ankle torque were measured after chronic stimulation. bEMS increased puromycin-labeled protein levels on day 3 post-injection (~1.5-2.0 fold; p < 0.05). After 10 days, bEMS mitigated reductions in muscle CSA in the gastrocnemius and tibialis anterior compared to the cachexia group. However, muscle strength (ankle torque) was not significantly improved. bEMS preserved muscle fiber size in cancer cachexia but failed to restore muscle function. These findings suggest bEMS may serve as a supportive strategy against muscle atrophy in cachectic conditions.

DOI: https://doi.org/10.1371/journal.pone.0336391
Mol Med. 2025 Nov 05. 31(1): 328

Syntaphilin loss enhances mitochondrial axonal transport and neuromuscular junction formation in a human stem cell derived neuromuscular assembloid model.

Andrea Salzinger, Esra Özkan, Vidya Ramesh, Jyoti Nanda, Karen Burr, David Story, Nhan T Pham, Siddharthan Chandran, Bhuvaneish T Selvaraj.

   BACKGROUND: The neuromuscular junction (NMJ) is the synapse between motor neurons and skeletal muscle and controlls movement. Impaired synaptic transmission and NMJ degeneration has been observed during healthy ageing and is also implicated in several neuromuscular diseases. On account of the high energy demands of being distally located and large sized, NMJs are enriched with mitochondria. This enrichment is dependent on transport of mitochondria across the axon to the NMJ.
METHODS: We first established a human 3D neuromuscular assembloid model to study in-vitro NMJs, by fusing human stem cell derived spinal cord organoids and primary skeletal muscle organoids. To determine whether enhancing axonal mitochondrial transport modulates NMJ formation and maintenance, we generated a CRISPR-Cas9 meditated knock-out of syntaphilin in human stem cells.
RESULTS: Firstly, we characterised the neuromuscular assembloid model which showed functional innervated NMJs as measured by juxtaposed neurofilament+ axons and α-bungarotoxin+ acetylcholine receptors. Secondly, we showed that spinal cord selective genetic ablation of syntaphilin - an axonally localised mitochondrial anchor protein - resulted in increased mitochondrial motility in motor neurons, and consequently increased axonal density and NMJ formation.
CONCLUSION: This proof-of-concept study demonstrated that enhancing mitochondrial mobility could provide a therapeutic target to prevent NMJ degeneration.

Keywords:  Assembloid; Axonal transport; Mitochondria; Neuromuscular diseases; Neuromuscular junction; Organoid; Stem cells

DOI:  https://doi.org/10.1186/s10020-025-01319-x
Physiol Rep. 2025 Nov;13(21): e70612

Retrospective transcriptomic analysis indicates temporal dysregulation of mitochondrial genes and metabolic pathways after volumetric muscle loss injury.

David L Miller, Sarah M Greising, Eugene F Douglas, Jarrod A Call.

  Volumetric muscle loss (VML) injury results in the irrecoverable loss of muscle mass and strength and alters the metabolic capacity of the remaining muscle tissue. The primary objective of this retrospective study was to leverage existing RNA-seq datasets to investigate mitochondria and metabolic transcriptome changes after VML injury. The datasets were extracted from publicly available sources and included a bulk RNA-seq dataset (Rattus norvegicus) and a single-cell RNA-seq dataset (Mus musculus) that combined provided a transcriptional landscape out to 42 days post-injury (dpi). The Broad Institute's MitoCarta3.0 database was used to identify mitochondrial-associated genes and pathways for the analysis. There was a robust downregulation of genes in the bulk RNA-seq dataset out to 28 dpi. Gene set enrichment analysis revealed that these genes contributed to oxidative phosphorylation, fatty-acid oxidation, and carbohydrate metabolism. A changing metabolic transcriptional landscape was evident in the single-cell RNA-seq dataset as several cell types (e.g., satellite cells, macrophages, and fibro-adipogenic cells) had upregulated gene sets (e.g., oxidative phosphorylation) that switched to downregulated after 14 dpi. Results from this study complement physiological studies that report dysfunctional mitochondrial bioenergetics, particularly for carbohydrate and free-fatty acid carbon sources, both immediately and chronically after VML injury. These findings also provide targets for monitoring the success of future interventions or directly manipulating in attempts to improve whole-muscle metabolic function.

Keywords:  mitochondria; muscle injury; muscle recovery; muscle regeneration; secondary data analysis

DOI:  https://doi.org/10.14814/phy2.70612
Geroscience. 2025 Nov 04.

Transcriptomic analysis of mitohormesis associated with lifespan extension in Caenorhabditis elegans.

Juri Kim, Naibedya Dutta, Gilberto Garcia, Ryo Higuchi-Sanabria.

  Non-lethal exposure to mitochondrial stress has been shown to have beneficial effects due to activation of signaling pathways, including the mitochondrial unfolded protein response (UPRmt). Activation of UPRmt restores the function of the mitochondria and improves general health and longevity in multiple model systems, termed mitohormesis. In C. elegans, mitohormesis can be accomplished by electron transport chain inhibition, a decline in mitochondrial translation, decreased mitochondrial import, and numerous other methods that activate UPRmt. However, not all methods that activate UPRmt promote longevity. These and other studies have started to question whether UPRmt is directly correlated with longevity. Here, we attempt to address this controversy by unraveling the complex molecular regulation of longevity of the nematode under different mitochondrial stressors that induce mitochondrial stress by performing RNA sequencing to profile transcriptome changes. Using this comprehensive and unbiased approach, we aim to determine whether specific transcriptomic changes can reveal a correlation between UPRmt and longevity. Altogether, this study will provide mechanistic insights on mitohormesis and how it correlates with the lifespan of C. elegans.

Keywords:  Aging; Caenorhabditis elegans; Mitohormesis; UPRmt

DOI:  https://doi.org/10.1007/s11357-025-01912-2
Support Care Cancer. 2025 Nov 07. 33(12): 1027

Effect of preoperative cancer cachexia on postoperative sarcopenia in patients with non-small cell lung cancer.

Kengo Shirado, Shota Okuno, Kenta Kawamitsu, Takashi Kido, Takako Eto, Manabu Yasuda, Toshihiro Yamashita.

   OBJECTIVE: Many patients with lung cancer have cancer cachexia, which may result in complications and affect prognosis; however, its preoperative prevalence is unknown. Skeletal muscle mass loss after lung cancer surgery also affects prognosis. Although cachexia and sarcopenia share some similarities, whether preoperative cachexia affects postoperative sarcopenia is still unknown. Thus, we designed a cohort study of patients with non-small cell lung cancer (NSCLC) to investigate this.
RESEARCH METHODS AND PROCEDURES: Patients with NSCLC who underwent surgery and perioperative rehabilitation were included in this study. The prevalence of preoperative cachexia and the association between preoperative cachexia and sarcopenia 1 month after surgery were tested using propensity-score matching. After matching, the regression analysis was performed to investigate whether preoperative cachexia was independently related to sarcopenia 1 month postoperatively.
RESULTS: In total, 126 patients (73 men) median age 71 (interquartile range 67, 76) years were included in the study. Preoperative cachexia was present in 16 (12.7%) patients, and postoperative sarcopenia was present in 29 (23%) patients. Among the 126 patients, 16 and 32 patients were included in the preoperative cachexia and control groups, respectively, as a result of matching (standardized mean difference < 0.1). After matching, regression analysis showed that preoperative cachexia was independently associated with sarcopenia at 1 month postoperatively (odds ratio 4.33, p = 0.020).
CONCLUSIONS: Among the patients with NSCLC, 12.7% had preoperative cachexia. Preoperative cachexia in patients with NSCLC affected sarcopenia 1 month postoperatively.

Keywords:  Cachexia; Non-small cell lung cancer; Rehabilitation; Sarcopenia; Surgery

DOI:  https://doi.org/10.1007/s00520-025-10089-5
Cell Metab. 2025 Nov 04. pii: S1550-4131(25)00480-2. [Epub ahead of print]

NAD depletion in skeletal muscle does not compromise muscle function or accelerate aging.

Sabina Chubanava, Iuliia Karavaeva, Amy M Ehrlich, Roger M Justicia, Astrid L Basse, Ivan Kulik, Emilie Dalbram, Danial Ahwazi, Samuel R Heaselgrave, Kajetan Trošt, Ben Stocks, Ondřej Hodek, Raissa N Rodrigues, Jesper F Havelund, Farina L Schlabs, Steen Larsen, Caio Y Yonamine, Carlos Henriquez-Olguín, Daniela Giustarini, Ranieri Rossi, Zachary Gerhart-Hines, Thomas Moritz, Juleen R Zierath, Kei Sakamoto, Thomas E Jensen, Nils J Færgeman, Gareth G Lavery, Atul S Deshmukh, Jonas T Treebak.

DOI: https://doi.org/10.1016/j.cmet.2025.10.020
Cell Death Differ. 2025 Nov 01.

Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.

Jose C Casas-Martinez, Qin Xia, Penglin Li, Maria Borja-Gonzalez, Antonio Miranda-Vizuete, Emma McDermott, Peter Dockery, Leo R Quinlan, Katarzyna Goljanek-Whysall, Afshin Samali, Brian McDonagh.

The transfer of information and metabolites between the mitochondria and the endoplasmic reticulum (ER) is mediated by mitochondria-ER contact sites (MERCS), allowing adaptations in response to changes in cellular homeostasis. MERCS are dynamic structures essential for maintaining cell homeostasis through the modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Under stress conditions such as ER protein misfolding, the Unfolded Protein Response (UPRER) mediates PERK and IRE1 activation, both of which localise at MERCS. Adaptive UPRER signalling enhances mitochondrial function and calcium import, whereas maladaptive responses lead to excessive calcium influx and apoptosis. In this study, induction of mild acute ER stress with tunicamycin (TM) in myoblasts promoted myogenesis that required PERK for increased MERCS assembly, mitochondrial turnover and function. Similarly, treatment of C. elegans embryos with an acute low concentration of TM, promoted an extension in lifespan and health-span. The adaptive ER stress response following a low dose of TM in both myoblasts and C. elegans, increased MERCS assembly and activated autophagy machinery, ultimately promoting an increase in mitochondrial remodelling. However, these beneficial adaptations were dependent on the developmental stage, as treatment of myotubes or adult C. elegans resulted in a maladaptive response. In both models the adaptations to UPRER activation were dependent on PERK signalling and its interaction with the UPRmt. The results demonstrate PERK is required for the increased mitochondrial ER communication in response to adaptive UPR signalling, promoting mitochondrial remodelling and improved physiological function.

DOI: https://doi.org/10.1038/s41418-025-01603-7
Front Mol Neurosci. 2025 ;18 1639114

Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline.

Zhanguo Su, Lijuan Xiang.

  The pathophysiology of neurodegenerative diseases is largely driven by ER stress, contributing to cellular dysfunction and inflammation. Chronic ER stress in skeletal muscle is associated with a deterioration in muscle function, particularly in diseases such as ALS, PD, and AD, which are often accompanied by muscle wasting and weakness. ER stress triggers the UPR, a cellular process designed to restore protein homeostasis, but prolonged or unresolved stress can lead to muscle degeneration. Recent studies indicate that exercise may modulate ER stress, thereby improving muscle health through the enhancement of the adaptive UPR, reducing protein misfolding, and promoting cellular repair mechanisms. This review examines the influence of exercise on the modulation of ER stress in muscle cells, with a particular focus on how physical activity influences key pathways contributed to mitochondrial function, protein folding, and quality control. We discuss how exercise-induced adaptations, including the activation of stress-resilience pathways, antioxidant responses, and autophagy, can help mitigate the negative effects of ER stress in muscle cells. Moreover, we examine the potential therapeutic implications of exercise in neurodegenerative diseases, where it may improve muscle function, reduce muscle wasting, and alleviate symptoms associated with ER stress. By integrating findings from neurobiology, muscle physiology, and cellular stress responses, this article highlights the therapeutic potential of exercise as a strategy to modulate ER stress and improve muscle function in neurodegenerative diseases.

Keywords:  ER stress; exercise; muscle function; neurodegenerative diseases; unfolded protein response

DOI:  https://doi.org/10.3389/fnmol.2025.1639114
Nature. 2025 Nov 05.

Secretome translation shaped by lysosomes and lunapark-marked ER junctions.

Heejun Choi, Ya-Cheng Liao, Young J Yoon, Jonathan Grimm, Nan Wang, Luke D Lavis, Robert H Singer, Jennifer Lippincott-Schwartz.

The endoplasmic reticulum (ER) is a highly interconnected membrane network that serves as a central site for protein synthesis and maturation1. A crucial subset of ER-associated transcripts, termed secretome mRNAs, encode secretory, lumenal and integral membrane proteins, representing nearly one-third of human protein-coding genes1. Unlike cytosolic mRNAs, secretome mRNAs undergo co-translational translocation, and thus require precise coordination between translation and protein insertion2,3. Disruption of this process, such as through altered elongation rates4, activates stress response pathways that impede cellular growth, raising the question of whether secretome translation is spatially organized to ensure fidelity. Here, using live-cell single-molecule imaging, we demonstrate that secretome mRNA translation is preferentially localized to ER junctions that are enriched with the structural protein lunapark and in close proximity to lysosomes. Lunapark depletion reduced ribosome density and translation efficiency of secretome mRNAs near lysosomes, an effect that was dependent on eIF2-mediated initiation and was reversed by the integrated stress response inhibitor ISRIB. Lysosome-associated translation was further modulated by nutrient status: amino acid deprivation enhanced lysosome-proximal translation, whereas lysosomal pH neutralization suppressed it. These findings identify a mechanism by which ER junctional proteins and lysosomal activity cooperatively pattern secretome mRNA translation, linking ER architecture and nutrient sensing to the production of secretory and membrane proteins.

DOI: https://doi.org/10.1038/s41586-025-09718-0
Cytokine. 2025 Dec;pii: S1043-4666(25)00207-8. [Epub ahead of print]196 157060

Clinical value and pro-inflammatory mechanism of miR-503-5p as a novel diagnostic biomarker for Sepsis.

Yanshan Liu, Tuo Xu, Yeting Zhang, Mali Fang.

   AIMS: Explore the expression of miR-503-5p in sepsis and its influence on the inflammatory response.
METHODS: A total of 120 patients with sepsis were retrospectively selected as the research subjects, and 80 healthy individuals were simultaneously selected as the control group. Reverse transcription quantitative polymerase chain reaction was used to detect the expression of miR-503-5p and related genes. Pearson correlation analysis was used to determine the relationships between variables, and multivariate logistic regression analysis was applied to analyze the risk factors associated with sepsis. Receiver operating characteristic curve analysis was performed to assess the diagnostic efficacy of serum miR-503-5p levels for sepsis. Sepsis-model cells were created in vitro for the purpose of exploring the possible action mechanism of miR-503-5p in the context of sepsis.
RESULTS: The expression of miR-503-5p in the serum of patients with sepsis is significantly upregulated, and it is positively correlated with the severity of the patients' condition and inflammatory indexes. miR-503-5p has a good diagnostic potential in sepsis. Furthermore, miR-503-5p exhibited a notable increase in expression within lipopolysaccharide (LPS)-stimulated THP-1 cells, which facilitated the inflammatory process. Mechanistically, miR-503-5p exacerbates the inflammatory response in sepsis via targeted suppression of peroxisome proliferator-activated receptor alpha (PPARA).
CONCLUSIONS: During sepsis, miR-503-5p shows elevated expression, and it facilitates the inflammatory response through the targeted suppression of PPARA.

Keywords:  Inflammation; PPARA; Sepsis; THP-1; miR-503-5p

DOI:  https://doi.org/10.1016/j.cyto.2025.157060