bims-musmir 2025-06-29 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–06–29
seventeen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Sex-dependent and muscle-specific progression of the MYBPC1 E248K Myotrem myopathy in response to aging.
Metabolic analysis of sarcopenic muscle identifies positive modulators of longevity and healthspan in C. elegans.
Vascular collapse leads to muscle wasting in cancer cachexia.
Restoration of myogenesis in ALS-myocytes through miR-26a-5p-mediated Smad4 inhibition and its impact on motor neuron development.
Chronic systemic inflammation by peptidoglycan-polysaccharide induces skeletal muscle atrophy in male and ovariectomized C57BL/6J mice.
OXA1L deficiency causes mitochondrial myopathy via reactive oxygen species regulated nuclear factor kappa B signalling pathway.
Concurrent Physical Activity Protects Against C26 Adenocarcinoma Tumor-Mediated Cardiac and Skeletal Muscle Dysfunction and Wasting in Males.
Muscle Spatial Transcriptomic Reveals Heterogeneous Profiles in Juvenile Dermatomyositis and Persistence of Abnormal Signature After Remission.
Enhancing Skeletal Muscle Fiber Type Transition Through Substrate Coating Alteration in Myoblast Cell Culture.
Mitochondrial pathology in inflammatory myopathies: a marker of worse clinical outcome.
Modulating the Gut-Muscle Axis: Increasing SCFA-Producing Gut Microbiota Commensals and Decreasing Endotoxin Production to Mitigate Cancer Cachexia.
Amino acid neurotransmitters in sarcopenia and healthy aging.
Plasma microRNA signatures of aging and their links to health outcomes and mortality: findings from a population-based cohort study.
Prognostic evaluation of GLIM-defined severe malnutrition via skeletal muscle mass index in critically ill adults: A comparative analysis.
Acute high-altitude hypoxia induced NLRP3 inflammasome activation in pulmonary artery smooth muscle cells by BMAL1 targeting mitochondrial VDAC1-mediated MtDNA leakage.
Oxidative Stress in Neurodegenerative Disorders: A Key Driver in Impairing Skeletal Muscle Health.
Sestrin2 improves intestinal ischemia-reperfusion injury through the TFEB-mediated autophagy/lysosomal pathway.

JCI Insight. 2025 Jun 26. pii: e182471. [Epub ahead of print]

Sex-dependent and muscle-specific progression of the MYBPC1 E248K Myotrem myopathy in response to aging.

Jennifer Megan Mariano, Humberto C Joca, Jacob G Kallenbach, Natasha Ranu, Julien Ochala, Christopher Ward, Aikaterini Kontrogianni-Konstantopoulos.

  Dominant missense mutations in MYBPC1, the gene encoding the essential sarcomeric slow Myosin Binding Protein-C (sMyBP-C), are associated with Myotrem, a new, early-onset congenital myopathy characterized by muscle weakness, hypotonia, skeletal deformities, and myogenic tremor. Importantly, the clinical manifestation of Myotrem in mid- and late adulthood is unknown. Using the Myotrem MYBPC1 E248K Knock-In (KI) murine model, we interrogated contractile performance of soleus, gastrocnemius, and Tibalis Anterior (TA) muscles in both male and female mice in mid- (12-months) and late (24-months) adulthood. Our findings showed that the phenotypic manifestation of E248K Myotrem differs across muscle-type, sex, and age. While KI soleus muscle consistently exhibited contractile impairment across both sexes and ages, KI gastrocnemius muscle displayed preserved force production. Interestingly, TA muscle showed a sex- and age-specific impact with preserved function through 12-months in both sexes and a sharp decline at 24-months solely in males. Quantitative analysis of TA sarcomeric organization uncovered structural deficits coinciding with contractile dysfunction, supporting the notion that sMyBP-C serves a primarily structural role in skeletal muscle. Collectively, our studies revealed that aging impacts the E248K Myotrem myopathy in a muscle- and sex-dependent fashion and show that sarcomeric disorganization accompanies contractile deterioration in affected muscles.

Keywords:  Cell biology; Cytoskeleton; Muscle biology; Neuromuscular disease; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.182471
Redox Biol. 2025 Jun 14. pii: S2213-2317(25)00245-9. [Epub ahead of print]85 103732

Metabolic analysis of sarcopenic muscle identifies positive modulators of longevity and healthspan in C. elegans.

Steffi M Jonk, Alan Nicol, Vicki Chrysostomou, Emma Lardner, Shu-Che Yu, Gustav Stålhammar, Jonathan G Crowston, James R Tribble, Peter Swoboda, Pete A Williams.

  Sarcopenia is the age-related degeneration of skeletal muscle, resulting in loss of skeletal muscle tone, mass, and quality. Skeletal muscle is a source of systemic metabolites and macromolecules important for neuronal health, function, and healthy neuronal aging. Age-related loss of skeletal muscle might result in decreased metabolite and macromolecule availability, resulting in reduced neuronal function or increased susceptibility to unhealthy aging and neurodegenerative diseases. We aimed to identify muscle metabolite candidates that regulate healthy aging. C57BL/6J mice were aged to young adult (4 months) and old age (25 months) and skeletal muscle was collected. Age-related muscle loss was confirmed by reduced muscle mass, muscle fiber degeneration, reduced myosin intensity, in addition to a metabolic shift and increased DNA damage in skeletal muscle. Using a low molecular weight enriched metabolomics protocol, we assessed the metabolic profile of skeletal muscle from young adult and old age mice and identified 20 metabolites that were significantly changed in aged muscle. These metabolite candidates were tested in C. elegans assays of lifespan, healthspan, muscle, and mitochondrial morphology under normal and stressed conditions. We identified four metabolite candidates (beta-alanine, 4-guanidinobutanoic acid, 4-hydroxyproline, pantothenic acid) that, when supplemented in C. elegans provided robust gero- and mitochondrial protection. These candidates also affected life-, and health- span in C. elegans models of amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD). Our findings support that aging muscle can be used to identify novel metabolite modulators of lifespan and health and may show promise for future treatments of neurodegenerative and neuromuscular disorders.

Keywords:  Aging; C. elegans; Metabolomics; Mitochondria; Sarcopenia

DOI:  https://doi.org/10.1016/j.redox.2025.103732
Nat Cancer. 2025 Jun 27.

Vascular collapse leads to muscle wasting in cancer cachexia.

Denis C Guttridge, Teresa A Zimmers.

DOI: https://doi.org/10.1038/s43018-025-01002-4
Mol Ther Nucleic Acids. 2025 Sep 09. 36(3): 102581

Restoration of myogenesis in ALS-myocytes through miR-26a-5p-mediated Smad4 inhibition and its impact on motor neuron development.

Caterina Peggion, Raphael Severino Bonadio, Roberto Stella, Silvia Scalabrin, Laura Pasetto, Caterina Millino, Laura Camporeale, Beniamina Pacchioni, Valentina Bonetto, Alessandro Bertoli, Stefano Cagnin, Maria Lina Massimino.

  Amyotrophic lateral sclerosis (ALS) is the most common adult-onset paralytic disorder, characterized primarily by a progressive loss of motor neurons (MNs) in which degeneration skeletal muscle involvement has been demonstrated. Skeletal muscle is a plastic tissue that responds to insults through proliferation and differentiation of satellite cells. Skeletal muscle degeneration and regeneration are finely regulated by signals that regulate satellite cell proliferation and differentiation. It is known that satellite cell differentiation is impaired in ALS, but little is known about the involvement of microRNAs (miRNAs) and their role in intercellular communication in ALS. Here we demonstrated impaired differentiation of satellite cells derived from ALS mice related to the impairment of myogenic p38MAPK and protein kinase A (PKA)/pCREB signaling pathways that can be regulated by miR-882 and -134-5p. These miRNAs participate in autocrine signaling in association with miR-26a-5p that, secreted from wild-type (WT) and captured by ALS myoblasts, enhances ALS-related myoblast differentiation by repressing Smad4-related signals. Moreover, miR-26a-5p and -431-5p work in a paracrine way ameliorating motoneuron differentiation. These findings emphasize the need to better understand intercellular communication and its role in ALS pathogenesis and progression. They also suggest that miRNAs could be targeted or used as therapeutic agents for myofiber and MN regeneration.

Keywords:  MT: non-coding RNAs; amyotrophic lateral sclerosis; cell communication; miRNA; myogenesis; neurogenesis; neuromuscular disorders; primary stem cells; skeletal muscle

DOI:  https://doi.org/10.1016/j.omtn.2025.102581
Physiol Rep. 2025 Jun;13(12): e70431

Chronic systemic inflammation by peptidoglycan-polysaccharide induces skeletal muscle atrophy in male and ovariectomized C57BL/6J mice.

Ryoga Kinoshita, Jay Jung, Sakura Hattori, Tatsuhiro Yamaguchi, Takaya Kotani, Karina Kouzaki, Yuki Tamura, Koichi Nakazato.

  Chronic systemic inflammation (CSI) induces skeletal muscle atrophy. The severity of tissue damage caused by CSI varies according to sex. However, there are still many unknowns regarding the sex differences in skeletal muscle atrophy in patients with CSI. This study aimed to determine the sex differences in CSI-induced muscle atrophy using male and female C57BL/6J mice. 12-week-old mice were divided into peptidoglycan-polysaccharide (PG-PS) (each sex, n = 9) and control groups (each sex, n = 10). In the ovariectomy (OVX) study, 8-week-old female C57BL/6J mice were divided into sham, OVX + Saline, and OVX + PG-PS groups (each group; n = 6). A single intraperitoneal injection of PG-PS or saline was administered to the mice. After 3 weeks, blood and lower leg skeletal muscles were collected. Plasma inflammatory cytokine levels were significantly increased in both sexes following PG-PS treatment. However, only male mice showed soleus muscle atrophy, decreased muscle protein synthesis (MPS), and increased apoptosis. In the OVX study, the OVX + PG-PS group exhibited soleus muscle atrophy caused by PG-PS-induced CSI. In atrophic muscles, PG-PS activated p65 and c-Jun. These findings suggest that ovarian function regulates muscle protein metabolism and suppresses CSI-induced skeletal muscle atrophy in female mice.

Keywords:  inflammation; sex difference; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.70431
Clin Transl Med. 2025 Jun;15(6): e70385

OXA1L deficiency causes mitochondrial myopathy via reactive oxygen species regulated nuclear factor kappa B signalling pathway.

Yongkun Zhan, Qian Wang, Ya Wang, Yanjie Fan, Dan Yan, Xianlong Lin, Yaoting Chen, Tingting Hu, Nan Li, Weiqian Dai, Hezhi Fang, Yongguo Yu.

   BACKGROUND: OXA1L is crucial for mitochondrial protein insertion and assembly into the inner mitochondrial membrane, and its variants have been recently linked to mitochondrial encephalopathy. However, the definitive pathogenic link between OXA1L variants and mitochondrial diseases as well as the underlying pathogenesis remains elusive.
METHODS: In this study, we identified bi-allelic variants of c.620G>T, p.(Cys207Phe) and c.1163_1164del, p.(Val388Alafs*15) in OXA1L gene in a mitochondrial myopathy patient using whole exome sequencing. To unravel the genotype-phenotype relationship and underlying pathogenic mechanism between OXA1L variants and mitochondrial diseases, patient-specific human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into myotubes, while OXA1L knockout human immortalised skeletal muscle cells (IHSMC) and a conditional skeletal muscle knockout mouse model was generated using clustered regularly interspaced short palindromic repeats/Cas9 genomic editing technology.
RESULTS: Both patient-specific hiPSC differentiated myotubes and OXA1L knockout IHSMC showed combined mitochondrial respiratory chain defects and oxidative phosphorylation (OXPHOS) impairments. Notably, in OXA1L-knockout IHSMC, transfection of wild-type human OXA1L but not truncated mutant form rescued the respiratory chain defects. Moreover, skeletal muscle conditional Oxa1l knockout mice exhibited OXPHOS deficiencies and skeletal muscle morphofunctional abnormalities, recapitulating the phenotypes of mitochondrial myopathy. Further functional investigations revealed that impaired OXPHOS resulting of OXA1L deficiency led to elevated reactive oxygen species production, which possibly activated the nuclear factor kappa B signalling pathway, triggering cell apoptosis.
CONCLUSIONS: Together, our findings reinforce the genotype-phenotype association between OXA1L variations and mitochondrial diseases and further delineate the potential molecular mechanisms of how OXA1L deficiency causes skeletal muscle deficits in mitochondrial myopathy.
KEYPOINTS: OXA1L gene bi-allelic variants cause mitochondrial myopathy. OXA1L deficiency results in combined mitochondrial respiratory chain defects and OXPHOS impairments. OXA1L deficiency leads to elevated ROS production, which may activate the NF-κB signalling pathway, disturbing myogenic gene expression and triggering cell apoptosis.

Keywords:  NF‐κB signalling pathway; OXA1L; mitochondrial myopathy; oxidative phosphorylation; reactive oxygen species

DOI:  https://doi.org/10.1002/ctm2.70385
Cells. 2025 Jun 18. pii: 924. [Epub ahead of print]14(12):

Concurrent Physical Activity Protects Against C26 Adenocarcinoma Tumor-Mediated Cardiac and Skeletal Muscle Dysfunction and Wasting in Males.

Louisa Tichy, Kimberly F Allred, Erika T Rezeli, Michael F Coleman, Clinton D Allred, Stephen D Hursting, Traci L Parry.

  Muscle loss unresponsive to nutritional supplementation affects up to 80% of cancer patients and severely reduces survival and treatment response. Exercise may help preserve muscle mass and function, yet the translatability of preclinical methods remains questionable. This study aimed to assess how voluntary wheel running, a clinically relevant physical activity, protects skeletal and cardiac muscle against cancer-mediated dysfunction and identify underlying molecular mechanisms.
METHODS: BALB/c mice were assigned to sedentary nontumor-bearing (SED+NT), sedentary tumor-bearing (SED+T), wheel run nontumor-bearing (WR+NT), and wheel run tumor-bearing (WR+T). Tumor-bearing groups received 5 × 105 C26 cells; WR mice had wheel access for 4 weeks. Muscle function and tissue were analyzed for protective mechanisms.
RESULTS: SED+T mice exhibited significant fat and lean mass loss, indicating cachexia, which was prevented in WR+T mice. SED+T also showed 15% reduced grip strength and cardiac dysfunction, while WR+T preserved function. WR+T mice had lower expression of muscle wasting markers (Atrogin1, MuRF1, GDF15, GDF8/11). Physical activity also reduced tumor mass by 57% and volume by 37%.
CONCLUSION: Voluntary wheel running confers tumor-suppressive, myoprotective, and cardioprotective effects. These findings support physical activity as a non-pharmacological strategy to combat cancer-related muscle wasting and dysfunction.

Keywords:  cancer; exercise; muscle wasting; physical activity; protection

DOI:  https://doi.org/10.3390/cells14120924
Cells. 2025 Jun 19. pii: 939. [Epub ahead of print]14(12):

Muscle Spatial Transcriptomic Reveals Heterogeneous Profiles in Juvenile Dermatomyositis and Persistence of Abnormal Signature After Remission.

Margot Tragin, Séverine A Degrelle, Baptiste Periou, Brigitte Bader-Meunier, Christine Barnerias, Christine Bodemer, Isabelle Desguerre, Mathieu Paul Rodero, François Jérôme Authier, Cyril Gitiaux.

  This study aimed to investigate the spatial heterogeneity of molecular signature in the muscle of juvenile dermatomyositis (JDM) patients before and after treatment. Unsupervised reference-free deconvolution of spatial transcriptomics and standardized morphometry were performed in two JDM muscle biopsies with different clinical severity at disease onset and compared to healthy muscle. Identified signatures were scored in two additional JDM muscle biopsies from the same patient before and after remission. Disappearance of the normal muscle signature mostly corresponding to mitochondrial biology was observed in JDM. Three pathological transcriptomic signatures were isolated, related to "myofibrillar stress", "muscle remodeling" and "interferon signaling" signatures. The "myofibrillar stress signature" was prominent in the most severe biopsy while the "muscle remodeling" signature was mostly present in the biopsy from the patient with good outcome. These signatures unveiled genes not previously associated with JDM including ANKRD1 and FSLT1 for "myofibrillar stress" and "muscle remodeling" signatures, respectively. Post-treatment analysis of muscle after two years remission showed a persistence of pathological signatures. This pilot study of JDM muscle identified spatially distributed pathological signatures that persist after remission. This work paves the way for a better understanding of the pathophysiology in affected muscle and the identification of biomarkers that predict relapse.

Keywords:  interferon; juvenile dermatomyositis; mitochondrial dysfunction; muscle spatial transcriptomic; visium

DOI:  https://doi.org/10.3390/cells14120939
Int J Mol Sci. 2025 Jun 12. pii: 5637. [Epub ahead of print]26(12):

Enhancing Skeletal Muscle Fiber Type Transition Through Substrate Coating Alteration in Myoblast Cell Culture.

Yhusi Karina Riskawati, Chuang-Yu Lin, Akira Niwa, Hsi Chang.

  Skeletal muscle diseases often exhibit fiber-type-specific characteristics and pose substantial clinical challenges, necessitating innovative therapies. The extracellular matrix (ECM) plays a pivotal role in muscle physiology and regeneration, influencing cell differentiation. However, its specific role and mechanisms influencing muscle fiber type specification remain insufficiently understood. In this study, C2C12GFP myoblasts were differentiated into myofibers on plates coated with fibronectin, Collagen I, and Geltrex™. Differentiation occurred successfully across all ECM substrates, resulting in myofiber formation. Quantitative polymerase chain reaction (qPCR) analysis confirmed myogenic marker expression patterns, indicating decreased Pax7 and increased Myog levels by day 7. Protein analysis through Western blot and immunofluorescence assays along with transcriptomic profiling through RNA sequencing consistently indicated that Collagen I promoted slow-type fibers development, as evidenced by increased slow myofiber protein expression and the upregulation of slow fiber-associated genes, potentially mediated by pathways involving calcineurin/NFAT, MEF2, MYOD, AMPK, PI3K/AKT, and ERK1. In contrast, fibronectin and Geltrex™ led to fast-type fiber development, with elevated fast-type fiber protein levels and upregulation of fast fiber-associated genes, possibly through activation of HIF1A, FOXO1, NFKB, and ERK2. These findings elucidate ECM-mediated muscle fiber type differentiation mechanisms, informing future targeted therapies for muscle regeneration.

Keywords:  Collagen I; Fibronectin; Geltrex™, C2C12 differentiation; muscle fiber type; transcriptomic

DOI:  https://doi.org/10.3390/ijms26125637
J Neurol. 2025 Jun 26. 272(7): 480

Mitochondrial pathology in inflammatory myopathies: a marker of worse clinical outcome.

Antonio Lauletta, Luca Bosco, Gioia Merlonghi, Yuri Matteo Falzone, Marta Cheli, Roberta Piera Bencivenga, Dario Zoppi, Marco Ceccanti, Felix Kleefeld, Sarah Léonard-Louis, Werner Stenzel, Olivier Benveniste, Lorenzo Maggi, Stefano Carlo Previtali, Matteo Garibaldi.

   OBJECTIVES: Mitochondrial dysfunction is well documented in inclusion body myositis (IBM), but its role in non-IBM myositis remains unclear. This study aimed to investigate the prevalence and clinical significance of mitochondrial pathology in non-IBM myositis and to assess its potential role as a marker for disease progression towards IBM, treatment response, and clinical outcomes.
METHODS: Muscle biopsies from 850 patients with inflammatory myopathy (IM) across 6 neuromuscular centers in Italy, France, and Germany were retrospectively analyzed. Inclusion required meeting diagnostic criteria for definite adult IM, mitochondrial pathology (age-exceeding numbers of COX-negative fibers), and exclusion of definite IBM according to Hilton-Jones 2013 criteria. The percentage of COX-negative fibers was quantified, correlated with clinical outcomes, and compared with myositis control cases without relevant signs of mitochondrial alterations.
RESULTS: Twenty-five patients with non-IBM myositis and mitochondrial abnormalities were identified. These patients, predominantly women (68%), had a mean onset age of 58.8 years. Polymyositis with mitochondrial pathology (PM-Mito) and nonspecific myositis (NSM) were the most prevalent subtypes (72%). The mean percentage of COX-negative fibers was 3% (0.25-8.5%) in these patients. The presence of mitochondrial pathology was associated with treatment refractoriness and worse clinical outcome evaluated based on residual muscle weakness and the level of independence (p < 0.005). A higher percentage of COX-negative fibers also correlated with poorer clinical outcomes (p = 0.031). Four patients, initially diagnosed with PM-Mito and NSM, progressed to definite IBM.
CONCLUSIONS: Mitochondrial dysfunction represents a key element informing about disease severity and poor clinical outcomes in non-IBM myositis. It may predict progression to IBM, especially in PM-Mito and NSM, and guide treatment strategies.

Keywords:  Inclusion body myositis (IBM); Inflammatory myopathies; Mitochondrial dysfunction; Polymyositis with mitochondrial pathology (PM-Mito)

DOI:  https://doi.org/10.1007/s00415-025-13192-z
Microorganisms. 2025 Jun 11. pii: 1356. [Epub ahead of print]13(6):

Modulating the Gut-Muscle Axis: Increasing SCFA-Producing Gut Microbiota Commensals and Decreasing Endotoxin Production to Mitigate Cancer Cachexia.

Sagnik Roy, Amir Hossein Alizadeh Bahmani, Mark Davids, Hilde Herrema, Max Nieuwdorp.

  Cancer cachexia is a multi-organ and multifactorial syndrome characterized by muscle wasting (with or without adipose tissue loss) and systemic inflammation in patients with advanced malignancies. Gut microbiota dysbiosis, particularly the depletion of short-chain fatty acid (SCFA)-producing bacteria, may contribute to the progression of cancer cachexia. Studies in both murine models and humans consistently associate cachexia with a decline in SCFA-producing gut microbiota commensals and an overgrowth of pro-inflammatory pathobionts. These microbial imbalances may lead to reduced levels of SCFAs and branched-chain amino acids (BCAAs) and alter the normal bile acid profile. BCAAs and the maintenance of a normal bile acid profile are associated with muscle synthesis and decreased breakdown. While SCFAs (acetate, propionate, and butyrate), contribute to intestinal barrier integrity and immune regulation. SCFA depletion may increase gut permeability, allowing bacterial endotoxins, such as lipopolysaccharide (LPS), to enter the bloodstream. This may lead to chronic inflammation, muscle catabolism, and impairment of anabolic pathways. Interventions targeting gut microbiota in preclinical models have mitigated inflammation and muscle loss. While clinical data are limited, it suggests an improvement in immune functions and better tolerance to anticancer therapies. Current evidence is predominantly derived from cross-sectional studies suggesting associations without causality. Thus, future longitudinal studies are needed to identify biomarkers and optimize personalized therapy.

Keywords:  bile acids; branched chain amino acids (BCAAs); cancer cachexia; dysbiosis; fecal microbiota transplantation; gut microbiota; inflammation; intestinal barrier integrity; microbiome-based therapies; prebiotics; probiotics; short-chain fatty acids (SCFAs); synbiotics

DOI:  https://doi.org/10.3390/microorganisms13061356
Brain Res Bull. 2025 Jun 20. pii: S0361-9230(25)00249-7. [Epub ahead of print]229 111437

Amino acid neurotransmitters in sarcopenia and healthy aging.

Steffi M Jonk, James R Tribble, Peter Swoboda, Pete A Williams.

  Sarcopenia is the age-related degeneration of skeletal muscle. Healthy skeletal muscle secretes metabolites and macromolecules that are systemically important for the immune system (e.g. myokines) and the central nervous system (e.g. BDNF). Exercise interventions to stimulate skeletal muscle are therapeutic for sarcopenia and limit risk and/or provide neuroprotection in neurodegenerative disease models. Metabolic analysis of aged skeletal muscle has identified altered skeletal muscle metabolomes at an old age. Many of the molecules identified are amino acids that also act as neurotransmitters. In this review, we summarize how 13 amino acids act as neurotransmitters or as precursor to neurotransmitters, and how these are involved in the skeletal muscle secretome, sarcopenia, and (healthy) aging.

Keywords:  Amino acids; Metabolomics; Muscle; Neurotransmitters; Sarcopenia

DOI:  https://doi.org/10.1016/j.brainresbull.2025.111437
Genome Med. 2025 Jun 25. 17(1): 70

Plasma microRNA signatures of aging and their links to health outcomes and mortality: findings from a population-based cohort study.

Lieke M Kuiper, Michelle M J Mens, Julia W Wu, Jaap Goudsmit, Yuan Ma, Liming Liang, Albert Hofman, Trudy Voortman, M Arfan Ikram, Jeroen G J van Rooij, Joyce B J van Meurs, Mohsen Ghanbari.

   BACKGROUND: MicroRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally and show differential expression in various tissues with aging phenotypes. Detectable in circulation, extracellular microRNAs reflect (patho)physiological processes and hold promise as biomarkers for healthy aging and age-related diseases. This study aimed to explore plasma extracellular microRNAs as a biological aging indicator and their associations with health outcomes using population-level data.
METHODS: We quantified plasma expression levels of 2083 extracellular microRNAs using targeted RNA-sequencing in 2684 participants from the population-based Rotterdam Study cohort. The training and test sets included 1930 participants from the advanced-aged initial and second subcohort (RS-I/RS-II; median age: 70.6), while the validation set comprised 754 participants from the middle-aged fourth subcohort (RS-IV; median age: 53.5). Based on 591 microRNAs well-expressed in plasma, we examined differential expression of microRNAs with chronological age, PhenoAge-a composite score of age and nine multi-system blood biomarkers-the frailty index, and mortality. Next, elastic net models were employed to construct composite microRNA-based aging biomarkers predicting chronological age (mirAge), PhenoAge (mirPA), frailty index (mirFI), and mortality (mirMort). The association of these aging biomarkers with different age-related health outcomes was assessed using Cox Proportional Hazard, linear regression, and logistic regression models in the test and validation sets.
RESULTS: We identified 188 microRNAs differentially expressed with chronological age within the RS-I/RS-II advanced-aged population (ntraining = 1158, ntest = 772), of which 177 microRNAs (94.1%) were replicated in the middle-aged RS-IV subcohort (nvalidation = 754). Moreover, 227 miRNAs showed robust associations with PhenoAge, 61 with FI, and 16 with 10-year mortality independent of chronological age. Subsequently, we constructed four plasma microRNA-based aging biomarkers: mirAge with 108, mirPA with 153, mirFI with 81, and mirMort with 50 miRNAs. Elevated scores on these microRNA-based aging biomarkers were associated with unfavorable health outcomes, including lower subjective physical functioning and self-reported health and increased mortality and frailty risk, but not with first- or multi-morbidity. Overall, larger effect estimates were observed for mirPA, mirFI, and mirMort compared to mirAge.
CONCLUSIONS: This study describes distinct plasma microRNA-aging signatures and introduces four microRNA-based aging biomarkers with the potential to identify accelerated aging and age-related decline, providing insights into the intricate process of human aging.

Keywords:  Aging; Biological age; Biomarker; Frailty; MicroRNA; Mortality

DOI:  https://doi.org/10.1186/s13073-025-01437-5
JPEN J Parenter Enteral Nutr. 2025 Jun 22.

Prognostic evaluation of GLIM-defined severe malnutrition via skeletal muscle mass index in critically ill adults: A comparative analysis.

Tomoka Miyagi, Minoru Yoshida, Shinya Suganuma, Kensuke Nakamura, Shunsuke Takaki.

   BACKGROUND: The Global Leadership Initiative on Malnutrition (GLIM) criteria are recommended by major academic societies; however, their application to critically ill patients is limited because of the difficulties associated with assessing muscle mass and the lack of standardized methods and cutoff values. We herein applied GLIM criteria to intensive care unit (ICU) patients by accurately assessing total skeletal muscle volume using computed tomography (CT) with sarcopenia diagnostic cutoff values.
METHODS: We included consecutive adult patients admitted to our ICU who underwent CT of the trunk. Total skeletal muscle area at the third lumbar vertebra was measured, and the skeletal muscle index was calculated. Reduced muscle mass was defined with Iritani criteria. A positive result in any of the phenotypic criteria was regarded as severe malnutrition. The primary outcome was in-hospital mortality. We also examined the agreement with the Subjective Global Assessment (SGA) using Cohen kappa coefficient.
RESULTS: Among 147 patients, 38 had weight loss, 39 had a low body mass index (BMI), and 41 had reduced muscle mass. In-hospital mortality was associated with reduced muscle mass (13.2% vs 43.9%, P < 0.001) and low BMI (15.7% vs 38.5%, P = 0.003). The concordance of individual and sole phenotypic criteria with SGA was low, whereas concordance was the highest at κ = 0.70 when all three criteria were combined.
CONCLUSIONS: GLIM criteria with accurate muscle mass evaluation using sarcopenia diagnostic cutoffs by CT may facilitate the identification of ICU patients with malnutrition whose prognosis is poor.

Keywords:  critical illness; intensive care unit; muscle; nutrition assessment

DOI:  https://doi.org/10.1002/jpen.2789
Apoptosis. 2025 Jun 22.

Acute high-altitude hypoxia induced NLRP3 inflammasome activation in pulmonary artery smooth muscle cells by BMAL1 targeting mitochondrial VDAC1-mediated MtDNA leakage.

Si-Yuan He, Ying-Rui Bu, Jin Xu, Yu-Meng Wang, Tian-Xi Feng, Pei-Jie Li, Yi-Xiao Zhao, Yi-Ling Ge, Man-Jiang Xie.

  Hypoxia-induced inflammatory injury is an important pathological mechanism underlying the progression of acute mountain sickness (AMS). Recent studies reported that molecular clock could control mitochondrial pathways to involve hypoxic and inflammatory responses. Excessively released mitochondrial DNA (mtDNA) acts as a damage-associated molecular pattern (DAMP) to trigger inflammation in many diseases. Herein, we subjected mice at a simulated altitude of 5500 m for 3 days and found that the expression levels of inflammatory cytokines were significantly increased in mouse pulmonary arteries, accompanied by mtDNA release and NLRP3 inflammasome activation in the pulmonary artery smooth muscle cells (PASMCs). RNA-sequencing and loss- and gain-of function experiments indicated that the core clock component BMAL1 regulated mtDNA leakage in PASMCs, and smooth muscle-specific Bmal1 knockout significantly alleviated the pulmonary arterial inflammation under acute high-altitude hypoxia. Mechanically, BMAL1 as a transcription factor directly promoted the transcriptional expression of Voltage-dependent anion channel 1 (VDAC1) and exacerbated the VDAC1-mediated mtDNA leakage under hypoxia, which activated NLRP3 inflammasome signaling in PASMCs and induced vascular inflammation. Our work provides mechanistic insights into the hypoxia-induced inflammation in PASMCs and may provide a novel therapeutic approaching for targeting BMAL1-VDAC1 in AMS.

Keywords:   Bmal1 ; High-altitude hypoxia; Inflammatory response; MtDNA leakage

DOI:  https://doi.org/10.1007/s10495-025-02138-5
Int J Mol Sci. 2025 Jun 16. pii: 5782. [Epub ahead of print]26(12):

Oxidative Stress in Neurodegenerative Disorders: A Key Driver in Impairing Skeletal Muscle Health.

Serena Castelli, Emily Carinci, Sara Baldelli.

  The fine regulation of antioxidant systems and intracellular production of reactive oxygen species (ROS) is responsible for cellular redox balance. The main organelles responsible for ROS production are mitochondria, and they complete this process through the electron transport chain. These potentially harmful molecules are buffered by enzymatic and non-enzymatic antioxidant systems. Oxidative stress is determined by an imbalance between the production and clearance of ROS in favor of the accumulation of these detrimental species, which generate cellular damage by interacting with macromolecules. In neurodegenerative diseases, oxidative stress has been demonstrated to be a crucial component, both causal and consequential to the disease itself. On the other hand, neurodegeneration disrupts neuromuscular junctions, leading to reduced muscle use and subsequent atrophy. Additionally, systemic inflammation and metabolic dysfunction associated with neurodegenerative diseases exacerbate muscle degeneration. Thus, sarcopenia and atrophy are common consequences of neurodegeneration and play a significant role in these disorders. Regarding this, ROS have been defined as promoting sarcopenia, stimulating the expression of genes typical of this condition. Overall, this review aims to contribute to filling the gap in the literature regarding the consequences at the muscular level of the relationship between oxidative stress and neurodegenerative diseases.

Keywords:  atrophy; neurodegenerative disease; oxidative stress; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3390/ijms26125782
Free Radic Biol Med. 2025 Jun 24. pii: S0891-5849(25)00787-7. [Epub ahead of print]

Sestrin2 improves intestinal ischemia-reperfusion injury through the TFEB-mediated autophagy/lysosomal pathway.

Jing-Yuan Xie, Man Ye, Jie Luo, Ning Hu, Yi-Guo Zhang, Le-le Zhang, Zi-Yi Wen, Xiang-Yun Fu, Rong Chen, Qing-Tao Meng.

  Sestrin2 is a stress-inducible protein that exhibits protective effects against ischemia-reperfusion injury in various organs. However, the specific roles and mechanisms of Sestrin2 in intestinal ischemia-reperfusion (IIR) injury have yet to be fully elucidated. The present study aims to investigate the role of Sestrin2 in intestinal IIR injury and its underlying mechanisms. We found that in the IIR model of C57BL/6J mice, Sestrin2 expression increased following IIR injury, accompanied by enhanced lysosomal activity and autophagy activation. Further cellular experiments demonstrated that overexpression of Sestrin2 increased autophagic flux, enhanced lysosomal activity, and mitigated cellular injury. These effects were abrogated by Sestrin2 knockdown. Additionally, we discovered that Sestrin2 interacts with transcription factor EB (TFEB), and that knockdown of Sestrin2 resulted in decreased nuclear translocation of TFEB, leading to a reduction in autophagic flux due to impaired lysosomal function. The TFEB activator (TFEB A1) promoted TFEB nuclear translocation and reversed autophagy/lysosomal pathway (ALP) dysfunction and cellular damage caused by Sestrin2 knockdown. In conclusion, Sestrin2 protects against IIR injury by promoting TFEB nuclear translocation, enhancing lysosomal activity, accelerating autophagosome turnover and substrate degradation, and increasing autophagic flux. These findings provide novel insights and potential targets for the treatment of IIR injury.

Keywords:  Intestinal ischemia-reperfusion; Lysosomal activation; Sestrin2; TFEB; autophagy

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.06.037