bims-musmir 2025-07-06 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–07–06
eleven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

The TWEAK/Fn14 signaling mediates skeletal muscle wasting during cancer cachexia.
Are Masters athletes the gold standard of ageing?
Pancreatic Cancer-Derived Extracellular Vesicles Enriched with miR-223-5p Promote Skeletal Muscle Wasting Associated with Cachexia.
Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and promote neuroprotection in the SOD1G93A mouse model of ALS through mechanisms involving IGF-Akt-mTOR signaling.
Histidine decarboxylase inhibition attenuates cancer-associated muscle wasting.
Fiber-specific differences in protein content of pathways related to mTORC1 signaling and oxidative metabolism in individuals with obesity.
Neuromuscular pathology and mitochondrial dysfunction in sorbitol dehydrogenase gene-related distal hereditary motor neuropathies.
Tissue-specific responses to TFAM and mtDNA copy number manipulation in prematurely ageing mice.
C9orf72 deficiency impairs the autophagic response to aggregated TDP-25 and exacerbates TDP-25-mediated neurodegeneration in vivo.
Mitochondrial DNA affects tau phosphorylation in aging and Alzheimer's disease.
Evaluating skeletal muscle wasting and weakness in models of critical illness.

iScience. 2025 Jul 18. 28(7): 112714

The TWEAK/Fn14 signaling mediates skeletal muscle wasting during cancer cachexia.

Meiricris Tomaz da Silva, Anirban Roy, Anh Tuan Vuong, Aniket S Joshi, Cristeena Josphien, Meghana V Trivedi, Sajedah M Hindi, Vihang A Narkar, Ashok Kumar.

  Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting. The TWEAK-Fn14 system regulates muscle mass in diverse conditions. However, its role in the regulation of muscle mass during cancer cachexia remains less understood. Here, we demonstrate that the levels of Fn14 are induced in skeletal muscle of multiple mouse models of cancer cachexia. Muscle-specific deletion of Fn14 reduces myofiber atrophy in mouse models of pancreatic and lung cancer cachexia. Silencing of Fn14 in KPC pancreatic cancer cells prior to their implantation in mice attenuates tumor growth without affecting myofiber size. Muscle-specific deletion of Fn14 reduces the gene expression of various components of the PERK and IRE1α arms of the unfolded protein response during KPC tumor growth. The inhibition of PERK improves protein synthesis and average myotube diameter in TWEAK-treated cultures. Altogether, our study suggests that the inhibition of TWEAK/Fn14 signaling can attenuate tumor growth and muscle wasting during cancer cachexia.

Keywords:  Cancer; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.112714
J Physiol. 2025 Jun 30.

Are Masters athletes the gold standard of ageing?

Dominique Greyvenstein, James P Newbold, Brandan K Wilson.



Keywords:  Masters athletes; ageing; exercise; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1113/JP289005
Adv Sci (Weinh). 2025 Jul 02. e04064

Pancreatic Cancer-Derived Extracellular Vesicles Enriched with miR-223-5p Promote Skeletal Muscle Wasting Associated with Cachexia.

Kangjing Xu, Rongxi Shen, Li Zhang, Xuejin Gao, Xinbo Wang, Changhua Zhang, Xi Chen, Xinying Wang.

  Pancreatic ductal adenocarcinoma (PDAC) with cachexia-related muscle wasting as the main manifestation is associated with poor overall survival. Extracellular vesicles (EVs) are key mediators of inter-organ communication. Here, EVs and EV-microRNAs (miRNAs) are identified as mediate PDAC-skeletal muscle communication. EVs are isolated from PDAC patients, mouse models, patients-derived organoids, and mouse pancreatic cancer cells. Plasma-derived EVs from PDAC patients or mice are observed to remarkably induced muscle wasting in vitro and in vivo. Depletion of miRNA cargo in these EVs significantly alleviates their detrimental effects on skeletal muscles. Deep RNA sequencing is conducted to profile differentially expressed miRNAs in plasma EVs from patients with or without PDAC. The findings reveal that the expression of miR-223-5p expression in PDAC patients' plasma EVs is negatively associated with the 3-year overall survival. Mechanistic studies show that miR-223-5p contributes to reduced METTL14 transcription by targeting MAFA, associated with decreased m6A methylation in skeletal muscles and muscle wasting. This study highlights the absorption of miRNA in PDAC-derived EVs by skeletal muscles and reveals a previously unrecognized function of PDAC-derived EV-miR-223-5p in tumor-muscle inter-organ communication, offering novel insight into EV-miR-223-5p-based diagnostic and therapeutic strategies for PDAC patients with sarcopenia upon further validation.

Keywords:  cancer cachexia; extracellular vesicles; miR‐223‐5p; muscle wasting; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1002/advs.202504064
Int J Biol Macromol. 2025 Jun 30. pii: S0141-8130(25)06200-2. [Epub ahead of print]319(Pt 4): 145645

Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and promote neuroprotection in the SOD1G93A mouse model of ALS through mechanisms involving IGF-Akt-mTOR signaling.

Ana Rodriguez-Romano, Juan Gonzalez-Valdivieso, Laura Moreno-Martinez, Juan Francisco Vázquez Costa, Rosario Osta, Patricia Rico.

  Amyotrophic Lateral Sclerosis (ALS) is a prevalent condition characterized by motor neuron loss and skeletal muscle paralysis. Despite being associated to mutations in over 40 genes, its etiology remains elusive without a cure or effective treatment. ALS, historically considered a motor neuron disease, is defined today as a multisystem disorder involving non-neuronal cell types, including early muscle pathology independent of motor neuron degeneration (dying back hypothesis), thus skeletal muscle actively contributes to disease pathology, making it a viable therapeutic target for ALS. Our previous research has shown that boron transporter NaBC1 (encoded by the SLC4A11 gene), after activation co-localizes with integrins and growth factor receptors synergistically enhancing muscle repair. Here we investigate the effects of injectable alginate-based hydrogels for controlled local borax release in Amyotrophic Lateral Sclerosis muscle. Treated mice showed improved motor function, prolonged survival, and activation of essential muscle metabolic pathways, leading to enhanced muscle repair and reduced atrophy and inflammation. Interestingly, local muscle repair activation provided retrograde neuroprotection by preserving motor neurons and reducing neuro-inflammation. This study highlights the role of muscle tissue in ALS pathology, supporting its targeting with NaBC1-based therapies for muscle regeneration.

Keywords:  ALS; Alginate hydrogel; Borax; Muscle regeneration; NaBC1 transporter (SLC4A11)

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.145645
J Exp Med. 2025 Sep 01. pii: e20242239. [Epub ahead of print]222(9):

Histidine decarboxylase inhibition attenuates cancer-associated muscle wasting.

Aneesha Dasgupta, Rebecca E Schmitt, Tatsuyoshi Kono, Chih-Chun Lee, Mark I Zoberi, Savannah A Epstein, Jessica Z Schneider, Alejandro Hernandez, Paul M Grandgenett, Thomas C Caffrey, Dominick J DiMaio, Michael A Hollingsworth, Jason D Doles.

Cancer cachexia is a multifactorial syndrome involving muscle and fat wasting, inflammation, and metabolic dysfunction. Across cancer subtypes, pancreatic cancer has one of the highest cachexia incidence rates at ∼80%. Given the advanced age of most pancreatic cancer patients, we sought to query cancer-associated muscle wasting using an age-matched murine model. We found that histamine and histamine decarboxylase (HDC) activity were specifically elevated in the muscles of aged tumor-bearing mice. We further found that (1) wasting stimuli induced histamine production and enhanced HDC activity; (2) exogenous histamine was sufficient to induce atrophy-associated gene expression; (3) inhibition of HDC activity by α-fluoromethylhistidine (FMH) protected against atrophy; (4) treatment of tumor-bearing mice with FMH rescued muscle wasting; and (5) a calcineurin inhibitor was able to rescue histamine-associated increases in calcium/atrogene signaling. In summary, we present a novel metabolic pathway that has significant implications for the treatment of cachectic cancer patients.

DOI: https://doi.org/10.1084/jem.20242239
Sci Rep. 2025 Jul 04. 15(1): 23839

Fiber-specific differences in protein content of pathways related to mTORC1 signaling and oxidative metabolism in individuals with obesity.

Cristian Campos, Marcelo Flores-Opazo, Denisse Valladares-Ide, Claudio Cabello-Verrugio, Pilar Parada, Francisco Morales, Joseline Arredondo, Luis Peñailillo.

  This study aimed to compare the protein content of pathways related to mTORC1 signaling and oxidative metabolism in whole skeletal muscle and isolated muscle fibers from healthy individuals (HEALTHY) and individuals with obesity (OBESE). Muscle biopsies were obtained from 18 individuals. Samples were freeze-dried, and fibers were isolated and fiber-typed for type I and IIa myosin heavy chain isoforms. The protein content of Akt-1, mTOR, p70s6K, S6 ribosomal protein (S6RP), ERK1/2, p38, total protein ubiquitination (TPU), and OXPHOS proteins in whole muscle and isolated fibers was determined using immunoblotting. Muscle fiber morphology was also assessed. Fiber type proportion was similar in HEALTHY, while OBESE showed a greater proportion of type IIa fibers. Fiber cross-sectional area (CSA) was similar in HEALTHY, while OBESE showed greater CSA of type I fibers. Protein content of p70s6K was lower (73%, p = 0.008), while ERK1/2 (29%, p = 0.05) and TPU (32%, p = 0.03) were increased in whole muscle from OBESE compared with HEALTHY. Fiber-specific differences were found in p38 (IIa > I, p = 0.03) in HEALTHY, while OBESE showed different complex II and V (I > IIa, p = 0.03 and p = 0.04, respectively) between fibers. Furthermore, a negative correlation was found between body mass and p70s6K protein content. Our findings suggest that obesity impairs the mTORC1-related protein pathway while increasing degradation in individuals with obesity.

Keywords:  Mitochondrial complex; Muscle protein synthesis; Muscle ubiquitination; Overweight; Skeletal muscle

DOI:  https://doi.org/10.1038/s41598-025-09169-7
J Neuropathol Exp Neurol. 2025 Jun 21. pii: nlaf070. [Epub ahead of print]

Neuromuscular pathology and mitochondrial dysfunction in sorbitol dehydrogenase gene-related distal hereditary motor neuropathies.

Zhenyu Li, Xujun Chu, Yize Li, Zhiying Xie, Meng Yu, Jianwen Deng, He Lv, Wei Zhang, Qiang Gang, Zhaoxia Wang, Lingchao Meng, Yun Yuan.

  Biallelic variants in sorbitol dehydrogenase (SORD) have been reported to be a major cause of autosomal recessive distal hereditary motor neuropathy (dHMN). In this study, the clinical and pathological features of 10 patients with SORD gene-related dHMN are reported. Homozygous c.757delG variant was detected in 6 patients while c.757delG, c.786 + 1G>A, c.218C>T, and a novel c.104T>A compound heterozygous variants were observed in the others. Serum sorbitol, xylitol, and D-arabinitol were measured by gas chromatography-mass spectrometry; increased sorbitol and xylitol, and decreased D-arabinitol were identified. Sural nerve biopsies showed mild loss of large, myelinated fibers, and a few thin myelinated fibers. Skeletal muscle biopsies exhibited a neurogenic pattern with vacuoles, tubular aggregates, and abnormal mitochondria. Proteomic analyses of muscle tissue were performed to explore potential mechanisms. Complex I deficiency was dominant in the proteomic analysis and the malic acid/oxaloacetic acid ratio was significantly higher in the patients than in controls. In summary, SORD gene-related dHMN is a systemic disorder of carbohydrate metabolism with subclinical myopathologic changes, including tubular aggregates and vacuoles. Mitochondrial complex I deficiency, may be a key mechanism in SORD gene-related dHMN.

Keywords:  SORD; carbohydrate metabolism; distal hereditary motor neuropathy; mitochondria; tubular aggregate

DOI:  https://doi.org/10.1093/jnen/nlaf070
Elife. 2025 Jun 30. pii: RP104461. [Epub ahead of print]14

Tissue-specific responses to TFAM and mtDNA copy number manipulation in prematurely ageing mice.

Laura Sophie Kremer, Guanbin Gao, Giovanni Rigoni, Roberta Filograna, Mara Mennuni, Rolf Wibom, Ákos Végvári, Camilla Koolmeister, Nils-Göran Larsson.

  Somatic mitochondrial DNA (mtDNA) mutations are implicated as important drivers of ageing and age-related diseases. Their pathological effect can be counteracted by increasing the absolute amount of wild-type mtDNA via moderately upregulating TFAM, a protein important for mtDNA packaging and expression. However, strong TFAM overexpression can also have detrimental effects as it results in mtDNA hypercompaction and subsequent impairment of mtDNA gene expression. Here, we have experimentally addressed the propensity of moderate TFAM modulation to improve the premature ageing phenotypes of mtDNA mutator mice, carrying random mtDNA mutations. Surprisingly, we detect tissue-specific endogenous compensatory mechanisms acting in mtDNA mutator mice, which largely affect the outcome of TFAM modulation. Accordingly, moderate overexpression of TFAM can have negative and beneficial effects in different tissues of mtDNA mutator mice. We see a similar behavior for TFAM reduction, which improves brown adipocyte tissue homeostasis, while other tissues are unaffected. Our findings highlight that the regulation of mtDNA copy number and gene expression is complex and causes tissue-specific effects that should be considered when modulating TFAM levels. Additionally, we suggest that TFAM is not the sole determinant of mtDNA copy number in situations where oxidative phosphorylation (OXPHOS) is compromised, but other important players must be involved.

Keywords:  biochemistry; chemical biology; genetics; genomics; mitochondrial DNA; mouse; mtDNA copy number; mtDNA mutations; tissue specificity

DOI:  https://doi.org/10.7554/eLife.104461
Acta Neuropathol Commun. 2025 06 28. 13(1): 136

C9orf72 deficiency impairs the autophagic response to aggregated TDP-25 and exacerbates TDP-25-mediated neurodegeneration in vivo.

Lilian Tsai-Wei Lin, Marc Shenouda, Philip McGoldrick, Agnes Lau, Janice Robertson.

  Cytoplasmic aggregates of the predominantly nuclear TAR DNA-binding protein 43 (TDP-43) are a pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) cases caused by G4C2 hexanucleotide repeat expansions in C9orf72 (C9-ALS/FTD). While these repeat expansions are associated with both gain- and loss-of-function mechanisms, the contribution of C9orf72 loss of function to disease pathogenesis remains unclear. C9orf72 has been shown to regulate autophagy, and its deficiency has been shown to exacerbate phenotypes in gain-of-function G4C2 models, implicating impaired autophagic clearance in disease pathogenesis. Here, we directly test whether C9orf72 deficiency exacerbates TDP-43 pathology and neurodegeneration in vivo. Using AAV9-vectors to drive neuron-specific expression of pathologically relevant C-terminal species of TDP-43, TDP-35 and TDP-25, we established models of TDP-43 pathology that recapitulate key disease features, including cytoplasmic aggregates, motor and cognitive decline, and neuronal loss. TDP-25 expression in particular produced robust, abnormally phosphorylated, ubiquitinated and p62-labelled cytoplasmic aggregates, modelling TDP-43 pathology in disease. Loss of C9orf72 in TDP-25-expressing mice accelerated the onset of motor deficits, increased neurodegeneration, and impaired the autophagic response to TDP-25 expression. These findings reveal that C9orf72 deficiency disrupts autophagy and exacerbates TDP-25-mediated toxicity in vivo, supporting a contributory role for C9orf72 loss-of-function in driving neurodegeneration in C9-ALS/FTD.

Keywords:  Amyotrophic lateral sclerosis; Autophagy; C9orf72; Frontotemporal dementia; Neurodegeneration; Protein aggregation; TAR DNA-binding protein 43

DOI:  https://doi.org/10.1186/s40478-025-02061-5
Alzheimers Dement. 2025 Jul;21(7): e70390

Mitochondrial DNA affects tau phosphorylation in aging and Alzheimer's disease.

Riley E Kemna, Paul J Kueck, Robyn Honea, Zachary Clark, Michaella Rekowski, Ian Weidling, Hana Mayfield, Casey S John, Jeffrey Burns, Heather M Wilkins, Russell Swerdlow, Jill K Morris.

   INTRODUCTION: Impaired mitochondrial function is seen in Alzheimer's disease (AD), but its role is unclear. Mitochondrial DNA (mtDNA) supports bioenergetic metabolism, but it is uncertain how it might influence AD neuropathology.
METHODS: We used cytoplasmic hybrid (cybrid) cell lines made from SH-SY5Y cells expressing mtDNA from cognitively healthy (CH), mild cognitive impairment (MCI), or AD individuals to investigate the impact of mtDNA-determined mitochondrial function on amyloid, tau, and neurodegeneration (ATN) markers. Cybrid measurements were correlated with cognition and brain morphometry.
RESULTS: Relative to cybrids expressing mtDNA from CH individuals, MCI and AD cybrids contained more phosphorylated tau-217 (p-tau217), p-tau181, and total tau. Cybrid p-tau217 correlated with plasma p-tau217 from the mtDNA donor (β = 0.605, p < 0.001). We observed negative relationships between cybrid p-tau217 and cognition and brain morphometry. MCI and AD cybrid proteomes showed mitochondrial dysfunction.
DISCUSSION: mtDNA-determined mitochondrial function affects cell physiology in AD-relevant ways. Our study suggests that mtDNA affects ATN status and clinical state.
HIGHLIGHTS: Mitochondrial DNA (mtDNA)-determined mitochondrial function drives Alzheimer's disease (AD) hallmarks. Cytoplasmic hybrid outcomes associate with mtDNA-donor clinical measures. Proteomic analyses indicate mitochondrial dysfunction in AD.

Keywords:  Alzheimer's disease; aging; biomarkers; metabolism; mitochondrial DNA

DOI:  https://doi.org/10.1002/alz.70390
Clin Sci (Lond). 2025 Jul 01. pii: CS20255458. [Epub ahead of print]139(13):

Evaluating skeletal muscle wasting and weakness in models of critical illness.

Amy J Bongetti, Marissa K Caldow, Yasmine Ali Abdelhamid, Gordon S Lynch.

  Skeletal muscle wasting and weakness are common complications associated with admission to the intensive care unit (ICU), with the loss of muscle mass and function increasing mortality and contributing to physical impairments post-discharge. While our understanding of the pathophysiology of this condition, commonly termed 'ICU-acquired weakness' (ICU-AW), has advanced considerably, no effective therapies are available. ICU-AW broadly encompasses a range of muscle-related impairments in this setting, including, but not limited to, critical illness myopathy and sepsis-induced myopathy. Pre-clinical models of critical illness can provide insights into the mechanisms underlying muscle wasting and weakness. Cell culture systems can provide mechanistic interrogation, by isolating effects to skeletal muscle directly. Small animal models, like rats and mice, allow for mechanistic investigation of ICU-AW using genetic models and testing pharmacological interventions. Larger animal models, including pigs and sheep, facilitate repeated blood and tissue sampling and can more closely recapitulate the standard-of-care within ICU settings. Although animal models can be advantageous for scientific investigation, they also have important limitations. Barriers to developing effective interventions include difficulty in obtaining muscle biopsies from patients, translating experimental findings between animal models and humans and replicating aspects of different ICU settings. This review explores the advantages and shortcomings of different pre-clinical models of critical illness, identifies gaps in understanding muscle wasting and weakness in critical illness and provides recommendations for improving the translation of therapeutics to promote functional recovery for patients post-discharge.

Keywords:  animal models; cell models; critical illness; inflammation; muscle wasting; muscle weakness; sepsis; skeletal muscle

DOI:  https://doi.org/10.1042/CS20255458