bims-musmir 2025-05-25 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2025–05–25
eleven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Global mitophagy inhibition via BNIP3 ablation is not sufficient to alleviate skeletal muscle impairments in male and female tumor-bearing mice.
Circadian rhythms in muscle health and diseases.
Sensitivity of miRNA-181a, miRNA-23b and miRNA-16 in the Late-Onset Neonatal Sepsis: A Diagnostic Study.
The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Low skeletal muscle and subcutaneous fat at admission are associated with 90-day mortality in intensive care unit patients.
COVID-19 Alters Inflammatory, Mitochondrial, and Protein Clearance Pathway Genes: Potential Implications for New-onset Parkinsonism in Patients.
Vascular and wound healing outcomes after puncture of small or stenotic inframalleolar arteries in patients with chronic limb-threatening ischemia.
The Influence of Sex on Fiber-Specific Indices of Oxidative Capacity in Human Skeletal Muscle.
Skeletal muscle TFEB overexpression does not increase neurogenesis markers in the young female hippocampus.
TRIM71 bound hsa-miR-30b-5p restores mitochondrial function in a cellular model of Parkinson's disease.
Metabolomics biomarkers of frailty: a longitudinal study of aging female and male mice.

J Appl Physiol (1985). 2025 May 16.

Global mitophagy inhibition via BNIP3 ablation is not sufficient to alleviate skeletal muscle impairments in male and female tumor-bearing mice.

Francielly Morena, Ana Regina Cabrera, Toby L Chambers, Pieter J Koopmans, Seongkyun Lim, Stavroula Tsitkanou, Sabin Khadgi, Calvin Peterson, Eleanor R Schrems, Ruqaiza Muhyudin, Sepideh Shakeri, Kevin Zhao, Devan Mishra, Tyrone Washington, Kevin A Murach, Nicholas P Greene.

  Cancer cachexia (CC) is marked by severe skeletal muscle loss and dysfunction, associated with mitochondrial degeneration. Our previous studies showed induction of the mitophagy marker BNIP3 3-weeks post-Lewis Lung Carcinoma (LLC) induction. We hypothesize excessive mitophagy contributes to muscle wasting in CC. To test this, we used a Bnip3 knockout (KO) mouse model with LLC-induced CC to assess its impact on muscle outcomes. 8-weeks-old male and female mice were injected with 1x106 LLC cells or PBS (sham controls). After 4 weeks, we assessed muscle function through dorsiflexor electrophysiology, muscle protein synthesis via deuterium oxide labeling, and mitochondrial respiration. Plantaris and white-gastrocnemius muscles were analyzed for mitochondrial respiratory function, tibialis anterior (TA) for muscle cross-sectional area, and mixed-gastrocnemius for protein and mRNA analysis. Bnip3 KO showed some benefits in males, including attenuated fat loss and splenomegaly and near-significant attenuation of EDL mass loss. In females, Bnip3 KO did not prevent relative muscle atrophy or functional impairments. In males, KO lowered protein synthesis independent of cancer. Despite KO reducing mitophagy markers, it did not improve muscle mitochondrial respiration or functional outcomes. In both sexes, KO mice exhibited unbalanced mitochondrial dynamics with increased fission and reduced fusion, processes also impaired by LLC. Overall, global Bnip3 ablation may not offer significant benefits for CC by itself. These findings suggest targeting aberrant mitophagy via complete Bnip3 deletion is insufficient to alleviate cancer-induced muscle detriments in both biological sexes, while BNIP3-mediated mitophagy may be needed to maintain protein anabolism.

Keywords:  Cachexia; Lung cancer; fractional synthesis rates; mitochondrial respiration; muscle contractility

DOI:  https://doi.org/10.1152/japplphysiol.00009.2025
Int Rev Cell Mol Biol. 2025 ;pii: S1937-6448(24)00153-9. [Epub ahead of print]393 45-72

Circadian rhythms in muscle health and diseases.

Jeffrey J Kelu.

  All major life forms from bacteria to humans have internal clocks that regulate essential biological processes in a roughly 24-h cycle. In mammals, the central clock in the suprachiasmatic nucleus (SCN) is historically considered the top of a hierarchical organisation that dominates subordinate clocks in peripheral tissues and dictates the circadian behaviours of an organism. Recent studies, however, underscore the importance of the local circadian oscillators, such as the skeletal muscle clock, in regulating local metabolism and physiology. Studies in animal models show that the muscle peripheral clock per se is required for the expression of genes involved in glucose, lipid, and amino acid metabolism. Disruption of the muscle clock leads to glucose intolerance, insulin resistance, and alterations in muscle size and force. This highlights the vital role of the muscle clock in controlling muscle physiology and metabolism. In humans, a perturbation in the muscle circadian rhythms is seen in metabolic disorders such as type 2 diabetes, and muscle diseases such as dystrophies. Disruption of muscle metabolism is also seen when the internal rhythms are misaligned with the external rhythms (circadian misalignments) as in shift work. Understanding the mechanisms by which the muscle clock regulates circadian functions may help the development of new strategies, such as chronotherapy, to potentially prevent or treat muscle pathologies and maintain muscle health.

Keywords:  Circadian clock; Metabolism; Muscle peripheral clock; Physiology

DOI:  https://doi.org/10.1016/bs.ircmb.2024.10.002
Matern Fetal Med. 2024 Oct;6(4): 243-248

Sensitivity of miRNA-181a, miRNA-23b and miRNA-16 in the Late-Onset Neonatal Sepsis: A Diagnostic Study.

Divya Katta, Kopula Satyamoorthy Sridharan, Uma Maheswari Balakrishnan, Prakash Amboiram, Kennedy Kumar.

   Objective: To evaluate the expression and diagnostic value of levels of the microRNAs (miRNAs), miRNA-181a, miRNA-23b, and miRNA-16, in late-onset neonatal sepsis (LOS) and compare them with the diagnostic utility of C-reactive protein (CRP) levels.
Methods: This was a prospective diagnostic study conducted between January 2021 and March 2023 at a tertiary care center (Sri Ramachandra Hospital) in India. Quantitative real-time polymerase chain reaction was performed to determine miRNA-181a, miRNA-23b, and miRNA-16 expression levels, and CRP was measured by nephelometry. The diagnostic value of miRNA and CRP levels were analyzed using receiver operating characteristic (ROC) curves. ROC curves were utilized to determine optimal cutoff points, and Mann-Whitney tests were performed using SPSS to ascertain P values, with statistical significance defined as <0.05.
Results: This study included 100 samples, with 50 cases of culture-proven LOS (27 females, 23 males) and 50 healthy controls (31 females, 19 males). In LOS, miRNA-181a and miRNA-23b expression levels were significantly downregulated (P < 0.001), with area under the curve (AUC) values of 0.83 and 0.92, respectively, whereas those of miRNA-16 were significantly upregulated (P < 0.001; AUC = 0.97). In comparison, CRP levels had an AUC value of 0.831 (P < 0.001). Further, miRNA-23b showed the highest sensitivity (98%) of markers tested, whereas miRNA-16 exhibited the highest specificity (96%).
Conclusion: MiRNA, especially miRNA-16, shows diagnostic potential for neonatal sepsis compared with traditional biomarkers like CRP and procalcitonin, suggesting its use as an early marker for LOS. However, further cohort studies are needed before practical application.

Keywords:  Biomarkers; Blood culture; Late-onset sepsis; MicroRNAs; Real-time PCR

DOI:  https://doi.org/10.1097/FM9.0000000000000227
Autophagy Rep. 2025 ;4(1): 2474796

The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Jimmy Beckers, Philip Van Damme.

  Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two extremes of a neurodegenerative disease spectrum characterised by overlapping genetic, clinical, and neuropathological features. This review covers the intricate relationship between both ALS and FTD and defects in the autophagy and endolysosomal pathway as recent evidence has pointed towards alterations in these pathways as being a root cause of disease pathogenesis. Here, we review the current knowledge on the interplay between ALS/FTD and lysosomebased proteostasis pathways and carefully asses the steps of the autophagy and endolysosomal pathways that are impaired by ALS or FTDcausing variants. Finally, we present a comprehensive overview of therapeutic strategies aimed at restoring autophagic and lysosomal function as potential avenues for mitigating the impact of these devastating diseases. Through this review, we aim to enhance the understanding of the pathophysiological mechanisms involving autophagy and/or the endolysosomal system that underlie the ALS-FTD spectrum and underscore the necessity for specific therapeutic approaches that target these shared vulnerabilities.

Keywords:  Amyotrophic lateral sclerosis (ALS); autophagosome; autophagy; endolysosome; endosome; frontotemporal dementia (FTD); lysosome; neurodegeneration

DOI:  https://doi.org/10.1080/27694127.2025.2474796
Clin Nutr ESPEN. 2025 May 16. pii: S2405-4577(25)00312-2. [Epub ahead of print]

Low skeletal muscle and subcutaneous fat at admission are associated with 90-day mortality in intensive care unit patients.

Ronan Thibault, Bruno Pereira, Mickaël Som, Ali Ait Hssain, Sylvain Dadet, Noël Cano, Bertrand Souweine.

   BACKGROUND: Low muscle mass assessed by the third lumbar vertebra (L3)-targeted abdominal computed tomography-scan (CT-scan) predicts short-term hospital mortality in the intensive care unit (ICU) patients. However, little is known regarding the relation between the L3 muscle and fat areas at ICU admission and 90-day clinical outcomes.
AIMS: to determine the relation between skeletal muscle, subcutaneous, visceral, intramuscular, and total fat cross-sectional areas at ICU admission and 90-day mortality (main), between skeletal muscle and other clinical outcomes, and between body mass index (BMI) and 90-day mortality (secondary).
METHODS: A retrospective observational study was performed in a 10-bed medical ICU. The inclusion criteria were: routine abdominal CT-scan <3 days post-admission, expected length of stay >48 hours. CT-scan assessed skeletal muscle, subcutaneous, visceral and intramuscular fat areas (cm2) at the L3 level. Low skeletal muscle index (SMI) was defined as <38.5 (women) and <52.4 cm2/m2 (men). Actuarial survival curves, univariate analyses and multivariable Cox models were performed.
RESULTS: Out of 200 screened patients, 141 were analyzed: age (mean±standard deviation) 65.2±14.9 years, 59% of males, Simplified Acute Physiology Score (SAPS) II 61.7±21.5, BMI, 27.9±6.4. Kaplan-Meier analysis indicated worse survival in patients with low skeletal SMI (61% (n=39/64) vs. 44 % (n=34/77), P=0.04). Cox multivariable analysis indicated that age ≥65 years (hazard ratio (HR)=1.82 [95% confidence interval, 1.03-3.23], P=0.04), SAPS II (HR=1.03 [1.02-1.04], P<0.001), low SMI (normal vs. low, HR=0.51 [0.31-0.87], P=0.01) and subcutaneous fat index log (HR=0.67 [0.49 - 0.91], P=0.01), were independently associated with 90-day mortality. Visceral, intramuscular and total fat areas were not associated with 90-day mortality. Higher body mass index was associated with lower 90-day mortality (HR=0.92 [0.88-0.96, P<0.001], when the model excluded muscle and fat tissue levels.
CONCLUSIONS: Lower skeletal muscle mass, subcutaneous fat and BMI at ICU admission are associated with higher 90-day mortality. Despite the Global Leadership Initiative on Malnutrition criteria were not used, these results suggest that protein-energy malnutrition at ICU admission is a strong marker of mortality.

Keywords:  body composition; critical care outcomes; critical illness; malnutrition; muscle proteins

DOI:  https://doi.org/10.1016/j.clnesp.2025.05.015
J Neuroimmune Pharmacol. 2025 May 22. 20(1): 58

COVID-19 Alters Inflammatory, Mitochondrial, and Protein Clearance Pathway Genes: Potential Implications for New-onset Parkinsonism in Patients.

Chukwunonso K Nwabufo.

  Several preclinical and clinical studies have shown that SARS-CoV-2 infection is associated with new-onset Parkinson's disease (PD). The overall goal of this study is to uncover how the COVID-19 severity gradient impacts the conventional pathological pathway of PD to inform the identification of at-risk patients and the development of personalized treatment strategies. Transcriptomics analysis of 43 PD pathogenic genes was conducted on nasopharyngeal swabs from 50 COVID-19 patients with varying severity including 17 outpatients, 16 non-ICU, and 17 ICU patients, compared to 13 SARS-CoV-2 negative individuals. The study shows that COVID-19 severity gradient differentially dysregulates PD pathological genes. Dysfunctional lysosomal and mitochondrial processes in outpatients and non-ICU COVID-19 patients was identified as the convergent network of COVID-19-PD interactions. These dysfunctions were later abrogated by the upregulation of the ubiquitin-proteasome system and autophagy-lysosome system in ICU COVID-19 patients. A potential synergistic co-expression and clustering of protein clearance pathway genes with other pathological genes was observed in ICU patients, indicating a possible overlap in biological pathways. Dysregulation of the PD pathopharmacogene, SLC6A3 was observed in ICU patients, suggesting potential COVID-19-gene-drug interactions. Nasopharyngeal swabs express major PD pathological genes as well as clinically relevant drug processing genes, which could advance studies on PD, including diagnosis, pathogenesis, and the development of disease-modifying treatments. Outpatients and non-ICU COVID-19 patients may face a higher risk of developing new-onset PD, whereas ICU COVID-19 patients may be more susceptible to COVID-19-gene-drug interactions.

Keywords:  Autophagy-lysosome system; COVID-19; COVID-19–Parkinson’s disease interactions; Disease–gene-drug interactions; Mitochondrial dysfunction; Nasopharyngeal swab; Parkinson’s disease; Pathopharmacogene; SARS-CoV-2; Ubiquitin–proteasome system; α-synuclein

DOI:  https://doi.org/10.1007/s11481-025-10215-4
J Vasc Surg. 2025 May 21. pii: S0741-5214(25)01103-6. [Epub ahead of print]

Vascular and wound healing outcomes after puncture of small or stenotic inframalleolar arteries in patients with chronic limb-threatening ischemia.

Shuko Iwata, Michinao Tan, Takashi Miwa, Wataru Sasaki, Kazushi Urasawa.

   OBJECTIVE: This study evaluated the safety of below-the-ankle distal punctures, including stenotic or small-diameter inframalleolar arteries, on vessel integrity and wound healing in patients with chronic limb-threatening ischemia and infrapopliteal artery disease.
METHODS: This single-center, retrospective, nonrandomized, observational study analyzed 171 limbs from 155 patients (mean age: 76.1 ± 9.4 years; 74.2% with diabetes mellitus; 48.4% undergoing hemodialysis) with chronic limb-threatening ischemia (Rutherford classification 5-6) who underwent endovascular therapy using below-the-ankle distal punctures for de novo infrapopliteal disease (97.1% occlusion) between January 2014 and December 2024.
RESULTS: Stenosis at puncture sites were observed in 83.0% of the cases, with a median vessel diameter of 1.8 mm. During a median follow-up of 13.1 months, the Kaplan-Meier-estimated 1-year wound healing rate was 57.3%. Chronic occlusion at puncture sites, defined as vessel occlusion after initial revascularization, occurred in 32.2% of the cases. Multivariate analysis identified renal failure on hemodialysis (odds ratio [OR]: 2.76; 95% confidence interval [CI]: 1.12-6.81; p = 0.028), the Global Limb Anatomical Staging System P2 modifier (OR: 2.89; 95% CI: 1.15-7.28; p = 0.024), and smaller distal puncture vessel sizes (scored as 0 [>2.0 mm], 1 [1.5-2.0 mm], or 2 [<1.5 mm]; OR: 10.8; 95% CI: 4.11-28.3; p < 0.001) as independent predictors of chronic occlusion at the puncture sites. The area under the receiver operating characteristic curve for vessel diameter in predicting chronic occlusion at the puncture site was 0.88, with the Youden J statistic indicating a cutoff value of 1.7 mm. Multivariate analysis showed that an increased foot infection grade (hazard ratio [HR]: 0.71; 95% CI: 0.51-0.99; p = 0.043), a small artery disease score of 2 (HR: 0.54; 95% CI: 0.30-0.98; p = 0.042), and a chronic occlusion at the puncture site (HR: 0.51; 95% CI: 0.28-0.92; p = 0.025) were independent risk factors for impaired wound healing.
CONCLUSIONS: Below-the-ankle distal punctures in stenotic arteries may cause puncture site occlusions before wound healing. If distal vessels at the puncture site supply the wound, close monitoring with Doppler or other imaging is essential to detect occlusions until the wound heals. When distal puncture is needed, selecting a target vessel with a larger diameter and minimal disease burden may lower the risk of chronic occlusions and help prevent delays in wound healing.

Keywords:  Angioplasty; Infrapopliteal Arteries; Ischemia; Punctures; Wound Healing

DOI:  https://doi.org/10.1016/j.jvs.2025.05.028
Am J Physiol Regul Integr Comp Physiol. 2025 May 23.

The Influence of Sex on Fiber-Specific Indices of Oxidative Capacity in Human Skeletal Muscle.

Celine Bailleul, Nathan Hodson, Sidney Abou Sawan, Dinesh Kumbhare, Daniel R Moore, Jenna B Gillen.

  There are reports that females compared to males display increased skeletal muscle oxidative capacity in resting mixed-muscle fiber samples from the vastus lateralis, including markers of mitochondrial content and capillarization. Given that sex comparisons at the mixed-fiber level may be explained by differences in muscle fiber type between males and females, it remains unclear if the oxidative capacity of type I and/or II fibers differ between sexes. The purpose of this study was to evaluate the influence of sex on fiber-specific indices of mitochondrial content and capillarization in healthy untrained males and females. Resting skeletal muscle samples from eumenorrheic females (n=14; 23±5yr; 23.3±3.2kg/m2) and males (n=13; 23±4yr; 23.1±2.4kg/m2) were analyzed via immunofluorescence staining. There were no sex differences in indices of capillarization (all p>0.06) or mitochondrial content (all p>0.42) in type I or type II muscle fibers. However, we observed lower capillary density in type II vs. type I muscle fibers in males (280±66 vs. 364±88 capillaries/mm2; p<0.001) but not females (335±77 vs. 329±48 capillaries/mm2; p=0.76), owing to greater cross-sectional area (CSA) of type II vs. type I fibers in males only (males p=0.03; females p=0.44). Females compared to males also displayed greater proportionate area of type I fibers (44±12 vs. 31±4%; p=0.03) and smaller CSA of type IIx fibers (3033±902 vs. 5573±1352 um2; p=0.002). Our results suggest that while muscle fiber-type composition and size differ between males and females, there are no sex differences in mitochondrial content and capillarization of type I or II muscle fibers in untrained adults.

Keywords:  capillarization; fiber composition; mitochondria; sex differences; skeletal muscle

DOI:  https://doi.org/10.1152/ajpregu.00298.2024
MicroPubl Biol. 2025 ;2025

Skeletal muscle TFEB overexpression does not increase neurogenesis markers in the young female hippocampus.

Mia Hakian, Ian Matthews, Constanza J Cortes.

Adult hippocampal neurogenesis (AHN), the process in which new neurons are formed in the dentate gyrus of the hippocampus, declines with age and is highly responsive to voluntary wheel running in mice. This exercise-activated increase in AHN is believed to contribute to the cognitive and neurotrophic benefits of exercise on the aging and neurodegenerative disease-afflicted brain. However, our current understanding of the decline in AHN remains male-centric, with very few studies examining the effects of age and/or running on AHN in the female brain. Our lab has recently shown that skeletal muscle-specific overexpression of Transcription Factor E-B (TFEB), a master regulator of lysosomal and mitochondrial function, mimics many of the neuroprotective benefits of exercise during aging and in the context of Alzheimer's disease (AD) pathologies, but the effect of muscle-TFEB overexpression on AHN was unknown. Here we report that female AHN declines in a similar timeline as to what has been reported for the male hippocampus, following a precipitous decline at around 3 months of age that culminates at around 8 months of age. Furthermore, we report that muscle-TFEB overexpression does not prevent this age-associated decrease in AHN, suggesting that the neuroprotective benefits observed in our muscle-TFEB model are independent of AHN.

DOI: https://doi.org/10.17912/micropub.biology.001612
Free Radic Biol Med. 2025 May 19. pii: S0891-5849(25)00677-X. [Epub ahead of print]

TRIM71 bound hsa-miR-30b-5p restores mitochondrial function in a cellular model of Parkinson's disease.

Shanikumar Goyani, Shatakshi Shukla, M V Saranga, Minal Mane, Nisha Chandak, Jyoti Singh, Pooja Jadiya, Dhanendra Tomar, Rajesh Singh.

  Nuclear-encoded mitochondrial-associated RNA-binding proteins (RBPs) play a key role in RNA stability and translation, which have also been implicated in various neurodegenerative disorders, including Parkinson's disease (PD). TRIM71, RING E3 Ligase, is known for its RNA-binding ability and transient interactions with mitochondrial surface. However miRNA binding and resulting effects on mitochondrial function and apoptosis in dopaminergic neurons, and their implications in PD pathogenesis have not yet been investigated. Here, we identified that TRIM71 binds to several miRNAs including miR-30b-5p on mitochondria of SH-SY5Y cells. The expression of miR-30b-5p is significantly increased in the presence of rotenone and reduced in the presence of 6-OHDA. The predicted gene targets of miR-30b-5p show specific networks involved in mitochondrial functions and apoptosis, including CASP3, BCL2, and BCL2L11, prominently associated with PD. The expression of miR-30b-5p decreased Caspase-3 levels in PD stress conditions, validating CASP3 as target mRNA. The expression of miR-30b-5p improved mitochondrial membrane potential and oxidative phosphorylation (OXPHOS) activity under PD stress conditions. miR-30b-5p also enhanced the oxygen consumption rate (OCR) as well as the glycolytic capacity and reserve PD stress conditions. Furthermore, the co-expression of miR-30b-5p with TRIM71 rescued TRIM71-mediated mitochondrial dysfunction and neuronal apoptosis, indicating a neuroprotective role. Together, these findings highlight that TRIM71-bound miR-30b-5p enhances mitochondrial function and attenuates apoptosis in PD stress conditions.

Keywords:  OCR; Parkinson’s disease (PD); ROS; cell death; miRNA; mitochondria

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.394
NPJ Aging. 2025 May 23. 11(1): 40

Metabolomics biomarkers of frailty: a longitudinal study of aging female and male mice.

Dantong Zhu, Judy Z Wu, Patrick T Griffin, Brady A Samuelson, David A Sinclair, Alice E Kane.

Frailty is an age-related geriatric syndrome. We performed a longitudinal study of aging female (n = 40) and male (n = 47) C57BL/6NIA mice, measured frailty index and derived metabolomics data from plasma. We identify age-related differentially abundant metabolites, determine frailty-related metabolites, and generate frailty features, both in the whole cohort and sex-stratified subgroups. Using the features, we perform an association study and build a metabolomics-based frailty clock. We find that frailty-related metabolites are enriched for amino acid metabolism and metabolism of cofactors and vitamins, include ergothioneine, tryptophan and alpha-ketoglutarate, and present sex dimorphism. We identify B vitamin metabolism related flavin-adenine dinucleotide and pyridoxate as female-specific frailty biomarkers, and lipid metabolism related sphingomyelins, glycerophosphoethanolamine and glycerophosphocholine as male-specific frailty biomarkers. These associations are confirmed in a validation cohort, with ergothioneine and perfluorooctanesulfonate identified as robust frailty biomarkers. Our results identify sex-specific metabolite frailty biomarkers, and shed light on potential mechanisms.

DOI: https://doi.org/10.1038/s41514-025-00237-w