bims-musmir 2025-03-30 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–03–30
eleven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

APOE4 exerts partial diet-dependent effects on energy expenditure and skeletal muscle mitochondrial pathways in a preclinical model.
Mito-Modulatory Medication Use and Skeletal Muscle Bioenergetics Among Older Men and Women: the Study of Muscle, Mobility and Aging.
Comparative Study of Structural and Functional Rearrangements in Skeletal Muscle Mitochondria of SOD1-G93A Transgenic Mice at Pre-, Early-, and Late-Symptomatic Stages of ALS Progression.
Pre-cachectic changes in amino acid homeostasis precede activation of eIF2α signaling in the liver at the onset of C26 cancer-induced cachexia.
Bioinformatics and machine learning approaches to explore key biomarkers in muscle aging linked to adipogenesis.
Chloroquine Causes Aging-like Changes in Diaphragm Neuromuscular Junction Morphology in Mice.
Whole-transcriptome sequencing in neural and non-neural tissues of a mouse model identifies miR-34a as a key regulator in SMA pathogenesis.
CREB3 gain of function variants protect against ALS.
Sex-dependent behavioral alterations in BALB/c mouse bearing a non-CNS solid tumor.
Loss of CTRP10 results in female obesity with preserved metabolic health.
MicroRNAs in the Mitochondria-Telomere Axis: Novel Insights into Cancer Development and Potential Therapeutic Targets.

Function (Oxf). 2025 Mar 25. pii: zqaf017. [Epub ahead of print]

APOE4 exerts partial diet-dependent effects on energy expenditure and skeletal muscle mitochondrial pathways in a preclinical model.

Chelsea N Johnson, Colton R Lysaker, Elaine C Gast, Colin S McCoin, Riley E Kemna, Kelly N Z Fuller, Benjamin A Kugler, Edziu Franczak, Vivien Csikos, Julie Allen, Casey S John, MaryJane A Wolf, Matthew E Morris, John P Thyfault, Heather M Wilkins, Paige C Geiger, Jill K Morris.

  Apolipoprotein E4 (APOE4) is the greatest genetic risk factor for Alzheimer's (AD) and is linked to whole-body metabolic dysfunction. However, it's unclear how APOE4 interacts with modifiable factors like diet to impact tissues central to regulating whole-body metabolism. We examined APOE4- and Western diet-driven effects in skeletal muscle using APOE3 (control) and APOE4 targeted replacement mice on a C57BL/6NTac background fed a high-fat diet (HFD, 45% kcal fat) or low-fat diet (LFD, 10% kcal fat) for four months (n=7-8 per genotype/diet/sex combination). We assessed body composition and whole-body outcomes linked to skeletal muscle function including respiratory exchange ratio (RER) and resting energy expenditure (REE). In skeletal muscle, we evaluated the proteome and mitochondrial respiration. In males only, APOE4 drove greater gains in fat mass and lower gains in lean mass on both diets. APOE4 did not affect daily RER but was associated with elevated REE in males and lower REE in HFD females after covarying for body composition. Skeletal muscle proteomics showed APOE4 exerts several diet- and sex-specific effects on mitochondrial pathways, including elevations in branched-chain amino catabolism in HFD males and reductions in oxidative phosphorylation in LFD females. This did not translate to differences in skeletal muscle mitochondrial respiration, suggesting that compensatory mechanisms may sustain mitochondrial function at this age. Our work indicates that genetic risk may mediate early life effects on skeletal muscle mitochondria and energy expenditure that are partially dependent on diet. This has important implications for mitigating AD risk in APOE4 carriers.

Keywords:   APOE4 ; Alzheimer's; mice; mitochondria; proteomics; skeletal muscle; whole-body metabolism

DOI:  https://doi.org/10.1093/function/zqaf017
J Gerontol A Biol Sci Med Sci. 2025 Mar 23. pii: glaf063. [Epub ahead of print]

Mito-Modulatory Medication Use and Skeletal Muscle Bioenergetics Among Older Men and Women: the Study of Muscle, Mobility and Aging.

Howard J Phang, Jaclyn Bergstrom, Rabia S Atayee, Laura A Hart, Peggy M Cawthon, Terri Blackwell, Philip A Kramer, Giovanna Distefano, Erin E Kershaw, Steven R Cummings, Anthony J A Molina.

   BACKGROUND: The potential impacts of drug-induced modulation of mitochondrial function in humans remain unclear despite the high prevalence of "mito-modulatory" medication use among older adults. While these medications, such as statins and metformin, have undergone extensive characterization of their effects on mitochondrial function in vitro, the effects in humans are far more complex and poorly understood.
METHODS: This study uses data from the Study of Muscle, Mobility and Aging (SOMMA) to evaluate how mito-modulatory medication use is related to skeletal muscle bioenergetic capacity, measured by ex vivo high-resolution respirometry and in vivo phosphorus magnetic resonance spectroscopy in healthy older adults.
RESULTS: We found that mito-modulatory medication use was related to lower maximal complex I&II supported oxidative phosphorylation (Max OXPHOS), maximal electron transfer system capacity (Max ETS), and maximal ATP production capacity (ATP Max) in men, but not in women. We also found this to be dependent on the number of medications used, in which higher mito-modulatory medication load was associated with lower Max OXPHOS, Max ETS, and ATP Max.
CONCLUSIONS: Our results provide greater insight into the potential clinical effects of mito-modulatory medication use and highlight the need to test the impact of these medications on mitochondrial function in randomized trials.

Keywords:  Medicine; Mitochondria; Polypharmacy

DOI:  https://doi.org/10.1093/gerona/glaf063
Front Biosci (Landmark Ed). 2025 Mar 18. 30(3): 28260

Comparative Study of Structural and Functional Rearrangements in Skeletal Muscle Mitochondria of SOD1-G93A Transgenic Mice at Pre-, Early-, and Late-Symptomatic Stages of ALS Progression.

Natalia V Belosludtseva, Anna I Ilzorkina, Mikhail V Dubinin, Irina B Mikheeva, Konstantin N Belosludtsev.

   BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive multisystem disease characterized by limb and trunk muscle weakness that is attributed, in part, to abnormalities in mitochondrial ultrastructure and impaired mitochondrial functions. This study investigated the time course of structural and functional rearrangements in skeletal muscle mitochondria in combination with motor impairments in Tg (copper-zinc superoxide dismutase enzyme (SOD1) G93A) dl1/GurJ (referred to as SOD1-G93A/low) male mice, a familial ALS model, as compared with non-transgenic littermates.
METHODS: The neurological status and motor functions were assessed weekly using the paw grip endurance method and the grid suspension test with two-limb and four-limb suspension tasks. Transmission electron microscopy followed by quantitative analysis was performed to study ultrastructural alterations in the quadriceps femoris. Functional analysis of skeletal muscle mitochondria was performed using high-resolution Oxygraph-2k (O2K) respirometry and methods for assessing the calcium retention capacity index and the content of lipid peroxidation products in freshly isolated preparations.
RESULTS: Based on the behavioral phenotyping data, specific age groups were identified: postnatal day 56 (P56) (n = 10-11), 84 (P84) (n = 10-11), and 156 (P154) (n = 10-12), representing the pre-symptomatic, early-symptomatic and late-symptomatic stages of ALS progression in SOD1-G93A/low mice, respectively. Electron microscopy showed mosaic destructive changes in subsarcolemmal mitochondria in fibers of the quadriceps femoris from 84-day-old SOD1-G93A/low mice. Morphometric analysis revealed an elevation in the mean size of the mitochondria in SOD1-G93A mice at P84 and P154. In addition, the P154 transgenic group demonstrated a decrease in sarcomere width and the number of mitochondria per unit area. At the symptomatic stage, SOD1-G93A mice exhibited a decreased respiratory control ratio, ADP-stimulated, and uncoupled respiration rates of mitochondria isolated from the quadriceps femoris muscle, as measured by high-resolution respirometry. In parallel, the mitochondria showed lower calcium retention capacity and increased levels of lipid peroxidation products compared with the control.
CONCLUSIONS: Taken together, these results indicate stage-dependent changes in skeletal muscle mitochondrial ultrastructure and functions associated with defective oxidative phosphorylation, impaired calcium homeostasis, and oxidative damage in the SOD1-G93A/low mouse model, which appears to be a promising direction for the development of combination therapies for ALS.

Keywords:  ALS; behavioral phenotyping; calcium retention capacity; lipid peroxidation; mitochondrial function; mouse SOD1*G93A model; pre-symptomatic stage; skeletal muscle mitochondria; symptomatic stage; ultrastructure

DOI:  https://doi.org/10.31083/FBL28260
iScience. 2025 Mar 21. 28(3): 112030

Pre-cachectic changes in amino acid homeostasis precede activation of eIF2α signaling in the liver at the onset of C26 cancer-induced cachexia.

Ghita Chaouki, Laurent Parry, Cyrielle Vituret, Céline Jousse, Martin Leremboure, Céline Bourgne, Laurent Mosoni, Yoann Delorme, Mehdi Djelloul-Mazouz, Julien Hermet, Julien Averous, Alain Bruhat, Lydie Combaret, Daniel Taillandier, Isabelle Papet, Laure B Bindels, Pierre Fafournoux, Anne-Catherine Maurin.

  The sequence of events associated with cancer cachexia induction needs to be further characterized. Using the C26 mouse model, we found that prior to cachexia, cancer progression was associated with increased levels of IL-6 and growth differentiation factor 15 (GDF15), highly induced production of positive acute phase proteins (APPs) and reduced levels of most amino acids in the systemic circulation, while signal transducer and activator of transcription 3 (STAT3) signaling was induced (1) in the growing spleen, alongside activation of ribosomal protein S6 (rpS6) and alpha subunit of eukaryotic translation initiation factor-2 (eIF2α) signalings, and (2) in the liver, alongside increased positive-APP expression, decreased albumin expression, and upregulation of autophagy. At the onset of cachexia, rpS6 and eIF2α signalings were concomitantly activated in the liver, with increased expression of activating transcription factor 4 (ATF4) target genes involved in amino acid synthesis and transport, as well as autophagy. Data show that pre-cachectic (pre-Cx) alterations in protein/aa homeostasis are followed by activation of eIF2α signaling in the liver, an adaptive mechanism likely regulating protein/amino acid metabolism upon progression to cachexia.

Keywords:  Cancer; Cell biology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2025.112030
BMC Musculoskelet Disord. 2025 Mar 22. 26(1): 285

Bioinformatics and machine learning approaches to explore key biomarkers in muscle aging linked to adipogenesis.

Yumin Zhang, Li Qin, Juan Liu.

  Adipogenesis is intricately linked to the onset and progression of muscle aging; however, the relevant biomarkers remain unclear. This study sought to identify key genes associated with adipogenesis in the context of muscle aging. Firstly, gene expression profiles from biopsies of the vastus lateralis muscle in both young and elderly population were retrieved from the GEO database. After intersecting with the results of differential gene analysis, weighted gene co-expression network analysis, and sets of adipogenesis-related genes, 29 adipogenesis-related differential expressed genes (ARDEGs) were selected. Connectivity Map (cMAP) analysis identified tamsulosin, fraxidin, and alaproclate as key target compounds. In further, using three machine learning algorithms and the friends analysis, four hub ARDEGs, ESRRA, RXRG, GADD45A, and CEBPB were identified and verified in vivo aged mice muscles. Immune infiltration analysis showed a strong link between several immune cells and hub ARDEGs. In all, these findings suggested that ESRRA, RXRG, GADD45A, and CEBPB could serve as adipogenesis related biomarkers in muscle aging.

Keywords:  Adipogenesis; Bioinformatics; Feature gene; Immune cell infiltration; Machine learning; Muscle aging; WGCNA analysis

DOI:  https://doi.org/10.1186/s12891-025-08528-9
Cells. 2025 Mar 07. pii: 390. [Epub ahead of print]14(6):

Chloroquine Causes Aging-like Changes in Diaphragm Neuromuscular Junction Morphology in Mice.

Chloe I Gulbronson, Sepideh Jahanian, Heather M Gransee, Gary C Sieck, Carlos B Mantilla.

  Autophagy impairments have been implicated in various aging conditions. Previous studies in cervical motor neurons show an age-dependent increase in the key autophagy proteins LC3 and p62, reflecting autophagy impairment and autophagosome accumulation. Chloroquine is commonly used to inhibit autophagy by preventing autophagosome-lysosome fusion and may thus emulate the effects of aging on the neuromuscular system. Indeed, acute chloroquine administration in old mice decreases maximal transdiaphragmatic pressure generation, consistent with aging effects. We hypothesized that chloroquine alters diaphragm muscle neuromuscular junction (NMJ) morphology and increases denervation. Adult male and female C57BL/6 × 129J mice between 5 and 8 months of age were used to examine diaphragm muscle NMJ morphology and denervation following daily intraperitoneal injections of chloroquine (10 mg/kg/d) or vehicle for 7 days. The motor end-plates and pre-synaptic terminals were fluorescently labeled with α-bungarotoxin and anti-synaptophysin, respectively. Confocal microscopy was used to assess pre- and post-synaptic morphology and denervation. At diaphragm NMJs, chloroquine treatment decreased pre-synaptic volume by 12% compared to the vehicle (p < 0.05), with no change in post-synaptic volume. Chloroquine treatment increased the proportion of partially denervated NMJs by 2.7-fold compared to vehicle treatment (p < 0.05). The morphological changes observed were similar to those previously reported in the diaphragm muscles of 18-month-old mice. These findings highlight the importance of autophagy in the maintenance of the structural properties at adult NMJs in vivo.

Keywords:  autophagy; diaphragm muscle; motor end-plate; neuromuscular junction; pre-synaptic terminal

DOI:  https://doi.org/10.3390/cells14060390
Mol Ther Nucleic Acids. 2025 Jun 10. 36(2): 102490

Whole-transcriptome sequencing in neural and non-neural tissues of a mouse model identifies miR-34a as a key regulator in SMA pathogenesis.

Liucheng Wu, Junjie Sun, Li Wang, Zhiheng Chen, Zeyuan Guan, Lili Du, Ruobing Qu, Chun Liu, Yixiang Shao, Yimin Hua.

  Spinal muscular atrophy (SMA) is a severe neurodegenerative disorder caused by deficiency of survival of motor neuron (SMN). While significant progress has been made in SMA therapy by rescuing SMN expression, limited knowledge about SMN downstream genes has hindered the development of alternative therapies. Here, we conducted whole-transcriptome sequencing of spinal cord, heart, and liver tissues of a severe SMA mouse model at early postnatal ages to explore critical coding and non-coding RNAs (ncRNAs). A large number of differentially expressed RNAs (DE-RNAs) were obtained, including 2,771 mRNAs, 382 microRNAs (miRNAs), 1,633 long ncRNAs, and 1,519 circular RNAs. Through in-depth data mining, we unveiled deregulation of miR-34a in all tissues. Analysis of competitive endogenous RNA networks of DE-RNAs identified multiple novel targets of miR-34a including Spag5 mRNA, lncRNA00138536, and circRNA007386. Further in vitro studies using mouse myoblast and human cardiomyocyte cell lines showed that knockdown of SMN upregulated miR-34a-5p and overexpression of miR-34a-5p alone disrupted cell-cycle progression through regulating its targets, recapitulating gene expression patterns observed in cardiac tissue of SMA mice. Our results identified a critical miRNA involved in SMA pathology, which sheds insights into the molecular basis of widespread tissue abnormalities observed in severe forms of SMA.

Keywords:  MT: Non-coding RNAs; SMN; Spag5; ceRNA network; cell cycle; miR-34a; spinal muscular atrophy

DOI:  https://doi.org/10.1016/j.omtn.2025.102490
Nat Commun. 2025 Mar 26. 16(1): 2942

CREB3 gain of function variants protect against ALS.

Salim Megat, Christine Marques, Marina Hernán-Godoy, Chantal Sellier, Geoffrey Stuart-Lopez, Sylvie Dirrig-Grosch, Charlotte Gorin, Aurore Brunet, Mathieu Fischer, Céline Keime, Pascal Kessler, Marco Antonio Mendoza-Parra, Ramona A J Zwamborn, Jan H Veldink, Sonja W Scholz, Luigi Ferrucci, Albert Ludolph, Bryan Traynor, Adriano Chio, Luc Dupuis, Caroline Rouaux.

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly evolving neurodegenerative disease arising from the loss of glutamatergic corticospinal neurons (CSN) and cholinergic motoneurons (MN). Here, we performed comparative cross-species transcriptomics of CSN using published snRNA-seq data from the motor cortex of ALS and control postmortem tissues, and performed longitudinal RNA-seq on CSN purified from male Sod1G86R mice. We report that CSN undergo ER stress and altered mRNA translation, and identify the transcription factor CREB3 and its regulatory network as a resilience marker of ALS, not only amongst vulnerable neuronal populations, but across all neuronal populations as well as other cell types. Using genetic and epidemiologic analyses we further identify the rare variant CREB3R119G (rs11538707) as a positive disease modifier in ALS. Through gain of function, CREB3R119G decreases the risk of developing ALS and the motor progression rate of ALS patients.

DOI: https://doi.org/10.1038/s41467-025-58098-6
Behav Brain Res. 2025 Mar 25. pii: S0166-4328(25)00142-1. [Epub ahead of print] 115556

Sex-dependent behavioral alterations in BALB/c mouse bearing a non-CNS solid tumor.

Isaias Gutierrez-Leal, Luisa M Onofre-Alvarado, Diana Caballero-Hernández, Ana L Cantu-Ruiz, Moises A Franco-Molina, Ricardo Gomez-Flores, Patricia Tamez-Guerra, Cristina Rodríguez-Padilla.

   BACKGROUND: Peripheral tumors can alter the central nervous system activity leading to behavior alterations and cancer-related cognitive impairment (CRCI). Although commonly attributed to anti-cancer treatments, findings of CRCI in newly diagnosed cancer patients suggest that tumors alone may impair brain functions, including working memory and processing speed.
METHODS: We assessed male and female mice behavior using a novel object recognition and a Y maze test along with the open field and burrowing tests. The tests were performed before and after tumor implantation (subcutaneous murine L5178Y-R lymphoma injection in the posterior hind limb), and through its progression to evaluate mobility, anxiety, motivation recognition, and spatial working memory.
RESULTS: Male mice showed deficits in recognition memory, scoring a low novel object time exploration (42.26% in males [p = 0.02] and 50.15% [p = 0.53] in females). Spontaneous alternation was significantly impaired in both male (p = 0.01) and female (p = 0.03) mice. During tumor progression, only female mice showed decreased mobility in indicators such as average speed, mobility rate, and total distance in the open field test, as well as deficient burrowing activity, indicating a lack of motivation or sickness behavior. Our findings suggest that tumor burden is associated with behavioral alterations in a sex-dependent manner in a mouse model of lymphoma.

Keywords:  CRCI; Cancer; behavior; cognitive impairment; lymphoma; sex differences

DOI:  https://doi.org/10.1016/j.bbr.2025.115556
Elife. 2025 Mar 24. pii: RP93373. [Epub ahead of print]13

Loss of CTRP10 results in female obesity with preserved metabolic health.

Fangluo Chen, Dylan C Sarver, Muzna Saqib, Leandro M Velez, Susan Aja, Marcus M Seldin, G William Wong.

  Obesity is a major risk factor for type 2 diabetes, dyslipidemia, cardiovascular disease, and hypertension. Intriguingly, there is a subset of metabolically healthy obese (MHO) individuals who are seemingly able to maintain a healthy metabolic profile free of metabolic syndrome. The molecular underpinnings of MHO, however, are not well understood. Here, we report that CTRP10/C1QL2-deficient mice represent a unique female model of MHO. CTRP10 modulates weight gain in a striking and sexually dimorphic manner. Female, but not male, mice lacking CTRP10 develop obesity with age on a low-fat diet while maintaining an otherwise healthy metabolic profile. When fed an obesogenic diet, female Ctrp10 knockout (KO) mice show rapid weight gain. Despite pronounced obesity, Ctrp10 KO female mice do not develop steatosis, dyslipidemia, glucose intolerance, insulin resistance, oxidative stress, or low-grade inflammation. Obesity is largely uncoupled from metabolic dysregulation in female KO mice. Multi-tissue transcriptomic analyses highlighted gene expression changes and pathways associated with insulin-sensitive obesity. Transcriptional correlation of the differentially expressed gene (DEG) orthologs in humans also shows sex differences in gene connectivity within and across metabolic tissues, underscoring the conserved sex-dependent function of CTRP10. Collectively, our findings suggest that CTRP10 negatively regulates body weight in females, and that loss of CTRP10 results in benign obesity with largely preserved insulin sensitivity and metabolic health. This female MHO mouse model is valuable for understanding sex-biased mechanisms that uncouple obesity from metabolic dysfunction.

Keywords:  Metabolism; computational biology; diabetes; genetics; genomics; insulin resistance; metabolically healthy obese; mouse; obesity; systems biology

DOI:  https://doi.org/10.7554/eLife.93373
Genes (Basel). 2025 Feb 25. pii: 268. [Epub ahead of print]16(3):

MicroRNAs in the Mitochondria-Telomere Axis: Novel Insights into Cancer Development and Potential Therapeutic Targets.

José Alfonso Cruz-Ramos, Emmanuel de la Mora-Jiménez, Beatriz Alejandra Llanes-Cervantes, Miguel Ángel Damián-Mejía.

  The mitochondria-telomere axis is recognized as an important factor in the processes of metabolism, aging and oncogenesis. MicroRNAs (miRNAs) play an essential function in this complex interaction, having an impact on aspects such as cellular homeostasis, oxidative responses and apoptosis. In recent years, miRNAs have been found to be crucial for telomeric stability, as well as for mitochondrial behavior, factors that influence cell proliferation and viability. Furthermore, mitochondrial miRNAs (mitomiRs) are associated with gene expression and the activity of the cGAS/STING pathway activity, linking mitochondrial DNA recognition to immune system responses. Hence, miRNAs maintain a link to mitochondrial biogenesis, metabolic changes in cancer and cellular organelles. This review focuses on the roles of a variety of miRNAs in cancer progression and their potential application as biomarkers or therapeutic agents.

Keywords:  cancer; carcinogenesis; microRNAs; mitochondria; mitomiRs; telomere; tumor progression

DOI:  https://doi.org/10.3390/genes16030268