bims-musmir 2024-12-22 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024–12–22
ten papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

ALDH3A1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to denervation and Amyotrophic Lateral Sclerosis progression.
Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
Muscle PGC-1α Overexpression Drives Metabolite Secretion Boosting Subcutaneous Adipocyte Browning.
Adipose-derived exosomes ameliorate skeletal muscle atrophy via miR-146a-5p/IGF-1R signaling.
Impact of exercise and fasting on mitochondrial regulators in human muscle.
Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function.
MicroRNA biogenesis pathway alterations in aging.
Association of plasma microRNAs with COVID-19 severity and outcome.
A blood-based mRNA signature distinguishes people with Long COVID from recovered individuals.
Skeletal muscle adaptations and post-exertional malaise in long COVID.

bioRxiv. 2024 Dec 02. pii: 2024.12.02.626422. [Epub ahead of print]

ALDH3A1-mediated detoxification of reactive aldehydes contributes to distinct muscle responses to denervation and Amyotrophic Lateral Sclerosis progression.

Ang Li, Li Dong, Xuejun Li, Jianxun Yi, Jianjie Ma, Jingsong Zhou.

  Different muscles exhibit varied susceptibility to degeneration in Amyotrophic Lateral Sclerosis (ALS), a fatal neuromuscular disorder. Extraocular muscles (EOMs) are particularly resistant to ALS progression and exploring the underlying molecular nature may deliver great therapeutic value. Reactive aldehyde 4-hydroxynonenal (HNE) is implicated in ALS pathogenesis and ALDH3A1 is an inactivation-resistant intracellular detoxifier of 4-HNE protecting eyes against UV-induced oxidative stress. Here we detected prominently higher levels of ALDH3A1 in mouse EOMs than other muscles under normal physiological conditions. In an ALS mouse model (hSOD1G93A) reaching end-stage, ALDH3A1 expression was sustained at high level in EOMs, whereas substantial upregulation of ALDH3A1 occurred in soleus and diaphragm. The upregulation was less pronounced in extensor digitorum longus (EDL) muscle, which endured the most severe pathological remodeling as demonstrated by unparalleled upregulation of a denervation marker ANKRD1 expression. Interestingly, sciatic nerve transection in wildtype mice induced ALDH3A1 and ANKRD1 expression in an inverse manner over muscle type and time. Adeno-associated virus enforced overexpression of ALDH3A1 protected myotubes from 4-HNE-induced DNA fragmentation, plasma membrane leakage and restored MG53-mediated membrane repair. Our data indicate that ALDH3A1 may contribute to distinct muscle resistance to ALS through detoxifying reactive aldehydes.

Keywords:  Reactive aldehydes; aldehyde dehydrogenase; amyotrophic lateral sclerosis; extraocular muscle; nuclear translocation; sciatic nerve transection

DOI:  https://doi.org/10.1101/2024.12.02.626422
Elife. 2024 Dec 20. pii: RP96926. [Epub ahead of print]13

Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.

Dylan C Sarver, Muzna Saqib, Fangluo Chen, G William Wong.

  Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanism underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: (1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; (2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; (3) age is a dominant factor affecting mitochondrial activity, especially across most brain regions, different fat depots, skeletal muscle groups, eyes, and different regions of the gastrointestinal tract; (4) age effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and (5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.

Keywords:  aging; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology

DOI:  https://doi.org/10.7554/eLife.96926
J Cell Physiol. 2024 Dec 15.

Muscle PGC-1α Overexpression Drives Metabolite Secretion Boosting Subcutaneous Adipocyte Browning.

Caterina Miro, Ciro Menale, Lucia Acampora, Annarita Nappi, Serena Sagliocchi, Federica Restolfer, Sepehr Torabinejad, Mariano Stornaiuolo, Monica Dentice, Annunziata Gaetana Cicatiello.

  Muscle and adipose tissue (AT) are in mutual interaction through the integration of endocrine and biochemical signals, thus regulating whole-body function and physiology. Besides a traditional view of endocrine relationships that imply the release of cytokines and growth factors, it is becoming increasingly clear that a metabolic network involving metabolites as signal molecules also exists between the two tissues. By elevating the number and functionality of mitochondria, a key role in muscle metabolism is played by the master regulator of mitochondrial biogenesis peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α), that induces a fiber type shift from glycolytic to oxidative myofibers. As a consequence, the upregulation of muscle respiratory rate might affect metabolite production and consumption. However, the underlying mechanisms have not yet been fully elucidated. Here, we used a muscle-specific PGC-1α overexpressing mouse model (MCK-PGC-1α) to analyze the metabolite secretion profile of serum and culture medium recovered from MCK-PGC-1α muscle fibers by NMR. We revealed modified levels of different metabolites that might be ascribed to the metabolic activation of the skeletal muscle fibers. Notably, the dysregulated levels of these metabolites affected adipocyte differentiation, as well as the browning process in vitro and in vivo. Interestingly such effect was exacerbated in the subcutaneous WAT, while only barely present in the visceral WAT. Our data confirm a prominent role of PGC-1α as a trigger of mitochondrial function in skeletal muscle and propose a novel function of this master regulator gene in modulating the metabolite production in turn affecting the activation of WAT and its conversion toward the browning.

Keywords:  PGC‐1α; adipocytes; browning; metabolites; skeletal muscle

DOI:  https://doi.org/10.1002/jcp.31480
J Nanobiotechnology. 2024 Dec 18. 22(1): 754

Adipose-derived exosomes ameliorate skeletal muscle atrophy via miR-146a-5p/IGF-1R signaling.

Mengran Qin, Jiahao Zhu, Lipeng Xing, Yaotian Fan, Junyi Luo, Jiajie Sun, Ting Chen, Yongliang Zhang, Qianyun Xi.

  The study of muscle disorders has gained popularity, with a particular emphasis on the relationship between adipose tissue and skeletal muscle. In our investigation, we discovered that the deletion of miR-146a-5p specifically in adipose tissue (aKO) led to a notable rise in mice's mass and adiposity. In contrast, it led to a decline in lean mass, ability to exercise, diameter of muscle fibers, and the levels of genes associated with differentiation. The co-culture experiment showed that the transfection of miR-146a-5p mimics to 3T3-L1 significantly suppressive cell growth and promotes myotube differentiation in C2C12 cells. Exosomes from white adipose tissue (WAT) of aKO mice (aKO-WAT-Exos) significantly promoted muscle atrophy and inhibited differentiation of C2C12 cells but were reversed by co-incubation with miR-146a-5p-mimics. The miR-146a-5p can specifically target IGF-1R to improve skeletal muscle wasting. In this process, the PI3K/AKT/mTOR pathway is activated or the FoxO3 pathway is inhibited to enhance the synthesis of skeletal muscle proteins. Significantly, miR-146a-5p serves a crucial function as a microRNA in the communication of the fat-muscle connection. It can be transported through the pathway of exosomes derived from adipose tissue, ultimately ameliorating skeletal muscle atrophy and modulating body mass index (BMI).

Keywords:  Adipose; Exosomes; IGF-1R; Muscle atrophy; Skeletal muscle; miR-146a-5p

DOI:  https://doi.org/10.1186/s12951-024-02983-7
Transl Exerc Biomed. 2024 Sep;1(3-4): 183-194

Impact of exercise and fasting on mitochondrial regulators in human muscle.

Eveline S Menezes, Hashim Islam, Benjamin B Arhen, Craig A Simpson, Chris McGlory, Brendon J Gurd.

   Objectives: To investigate the impact of acute energetic stress (acute HIIE and fasting) on ERRγ, PPARβ, NR1D1, NR4A1, and TFEB in human skeletal muscle.
Methods: The current study performed secondary analyses using muscle biopsy samples from two previously published studies: study 1) leg muscle biopsies from nine men and eight women were obtained pre and 3 h following acute high-intensity interval cycling exercise (HIIE); study 2) leg muscle biopsies were obtained from nine men pre-, during, and post-an 8 h fast with or without 2 h of arm ergometer exercise. RT-PCR was performed on samples from each study to determine the mRNA expression of ERRγ, PPARβ, NR1D1, NR4A1, and TFEB. Additionally, we retrieved data from meta-analyzed human muscle gene expression using the publicly available database MetaMex.
Results: PGC-1α (p<0.01, d=1.98) and NR4A1 (p<0.01, d=1.36) mRNA expression significantly increased while TFEB (p≤0.05, d=0.70) decreased following HIIE. Significant decreases in NR4A1 and NR1D1 mRNA expression were observed following an 8 h fast. Our MetaMex analyses revealed significant increases (p<0.05) in PGC-1α and NR4A1 expression following aerobic and resistance exercise, and in PPARβ expression following resistance exercise.
Conclusions: Our data indicate that acute HIIE stimulates increases in NR4A1 and PGC-1α and decreases in TFEB mRNA expression in human skeletal muscle. Additionally, a short term (8 h) fast reduced the mRNA expression of the transcriptional regulators NR4A1 and NR1D1 - potentially as a mechanism of decreasing mitochondrial biogenesis to reduce energy expenditure during a period of restricted energy availability.

Keywords:  aerobic exercise; caloric restriction; food deprivation; muscle remodeling; transcriptional regulators

DOI:  https://doi.org/10.1515/teb-2024-0014
Redox Biol. 2024 Dec 12. pii: S2213-2317(24)00445-2. [Epub ahead of print]79 103467

Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function.

Chao Song, Wu Zheng, Guoming Liu, Yiyang Xu, Zhibo Deng, Yu Xiu, Rongsheng Zhang, Linhai Yang, Yifei Zhang, Guoyu Yu, Yibin Su, Jun Luo, Bingwei He, Jie Xu, Hanhao Dai.

  In aging and metabolic disease, sarcopenic obesity (SO) correlates with intramuscular adipose tissue (IMAT). Using bioinformatics analysis, we found a potential target protein Extended Synaptotagmin 1 (E-syt1) in SO. To investigate the regulatory role of E-syt1 in muscle metabolism, we performed in vivo and in vitro experiments through E-syt1 loss- and gain-of-function on muscle physiology. When E-syt1 is overexpressed in vitro, myoblast proliferation, differentiation, mitochondrial respiration, biogenesis, and mitochondrial dynamics are impaired, which were alleviated by the silence of E-syt1. Furthermore, overexpression of E-syt1 inhibited mitophagic flux. Mechanistically, E-syt1 overexpression leads to mitochondrial calcium overload and mitochondrial ROS burst, inhibits the fusion of mitophagosomes with lysosomes, and impedes the acidification of lysosomes. Animal experiments demonstrated the inhibition of E-syt1 increased the capacity of endurance exercise, muscle mass, mitochondrial function, and oxidative capacity of the muscle fibers in OVX mice. These findings establish E-syt1 as a novel contributor to the pathogenesis of skeletal muscle metabolic disorders in SO. Consequently, targeting E-syt1-induced dysfunction may serve as a viable strategy for attenuating SO.

Keywords:  E-syt1; Mitochondria; Mitophagy; Myogenesis; Sarcopenic obesity

DOI:  https://doi.org/10.1016/j.redox.2024.103467
Extracell Vesicles Circ Nucl Acids. 2023 ;4(3): 486-501

MicroRNA biogenesis pathway alterations in aging.

Jorge Sanz-Ros, Cristina Mas-Bargues, Nekane Romero-García, Javier Huete-Acevedo, Mar Dromant, Consuelo Borrás.

  Aging is characterized by genomic instability and dysregulation of gene expression. MicroRNAs (miRNAs) are small non-coding RNAs that play a crucial role in post-transcriptional gene regulation. This work explores the impact of dysregulated miRNA biogenesis on the aging process. During aging, alterations in the transcription of primary miRNAs (pri-miRNAs) occur due to genomic changes, DNA damage, and epigenetic modifications. The microprocessor complex, comprising DGCR8 and Drosha proteins, is vital for pri-miRNA processing. Age-related changes in this complex affect miRNA biogenesis and miRNA expression profiles, linking these alterations with age-related conditions. Conversely, interventions like caloric restriction and mTOR inhibition enhance microprocessor activity, suggesting a connection between microprocessor function, aging-related pathways, and lifespan extension. Exportin-5 mediates the transport of pre-miRNAs from the nucleus to the cytoplasm. Although the role of miRNA export in aging is not well understood, accelerated export of pre-miRNAs is observed in response to DNA damage, and nucleocytoplasmic transport has been linked to cellular senescence. Dicer is responsible for processing pre-miRNAs into mature miRNAs. Reduced Dicer expression during aging is reported in various organisms and tissues and is associated with premature aging phenotypes. Conversely, the upregulation of Dicer improves stress resistance and metabolic adaptations induced by caloric restriction and exercise training. Understanding the role of miRNA biogenesis disruption in aging provides insights into the molecular mechanisms of aging and age-related diseases. Targeting this pathway may hold promise for therapeutic strategies and contribute to healthy aging.

Keywords:  MicroRNA biogenesis; aging process; intercellular communication; lifespan

DOI:  https://doi.org/10.20517/evcna.2023.29
J Genet Eng Biotechnol. 2024 Dec;pii: S1687-157X(24)00136-7. [Epub ahead of print]22(4): 100433

Association of plasma microRNAs with COVID-19 severity and outcome.

Sohair Salem, Randa Lotfy, Noha Eltaweel, Mohamed Elbadry.

   OBJECTIVE: As one of the remarkable host responses to SARS-CoV-2 infection, circulating microRNAs (miRNAs) represent important diagnostic and prognostic diseases biomarkers. The study is a step towards highlighting the role of miRNAs in COVID-19 pathogenesis and severity.
METHODS: In this case-control study, miRCURY LNA miRNA PCR plasma panel (168 miRNAs) was applied and the expression of the altered miRNAs was then analysed by quantitative real time PCR for 120 COVID-19 patients (30 mild, 30 moderate, 30 severe, and 30 critical) and 30 healthy subjects.
RESULTS: The initial screening showed that 30 miRNAs displayed altered expression, out of them, only eleven miRNAs (miR-885-5p, miR-141-3p, miR-21-5p, miR-127-3p, miR-99b-5p, let-7d-3p, miR-375, miR-1260a, miR-139-5p, miR-28-5p and miR-34a-5p) were dysregulated in the plasma of COVID-19 patients; all of them were significantly overexpressed. By applying ROC curve analysis, AUC for the eleven miRNAs were ranged from 0.65 to 0.83, and the AUC for the combined miRNAs was 0.93. Ten miRNAs (miR-141-3p, miR-181a-5p, miR-221-3p, miR-223-5p, miR99b-5p, Let-7d-3p, miR-375, miR-199a-5p, miR-139-5p and miR-28-5p) exhibited a significant change in their expression between different severity groups. Patients with positive outcome were found to have increased miR-375 and decreased miR-99b-5p expression levels. Bioinformatic prediction showed that, out of the eleven dysregulated miRNAs, five miRNAs (miR-139-5p, -34a-5p, -28-5p, -21-5p and -885-5p) have the ability to regulate at least two genes related to COVID-19 according to KEGG database.
CONCLUSION: miRNAs are dysregulated in COVID-19 patients and associated with severity degree and patients' outcome.

Keywords:  COVID-19; Outcome; Severity; microRNAs

DOI:  https://doi.org/10.1016/j.jgeb.2024.100433
Front Immunol. 2024 ;15 1450853

A blood-based mRNA signature distinguishes people with Long COVID from recovered individuals.

Daniel Missailidis, Esmaeil Ebrahimie, Manijeh Mohammadi Dehcheshmeh, Claire Allan, Oana Sanislav, Paul Fisher, Stephanie Gras, Sarah J Annesley.

   Introduction: Long COVID is a debilitating condition that lasts for more than three months post-infection by SARS-CoV-2. On average, one in ten individuals infected with SARS CoV- 2 develops Long COVID worldwide. A knowledge gap exists in our understanding of the mechanisms, genetic risk factors, and biomarkers that could be associated with Long COVID.
Methods: In this pilot study we used RNA-Seq to quantify the transcriptomes of peripheral blood mononuclear cells isolated from COVID-recovered individuals, seven with and seven without Long COVID symptoms (age- and sex-matched individuals), on average 6 months after infection.
Results: Seventy genes were identified as significantly up- or down-regulated in Long COVID samples, and the vast majority were downregulated. The most significantly up- or downregulated genes fell into two main categories, either associated with cell survival or with inflammation. This included genes such as ICOS (FDR p = 0.024) and S1PR1 (FDR p = 0.019) that were both up-regulated, indicating that a pro-inflammatory state is sustained in Long COVID PBMCs compared with COVID recovered PBMCs. Functional enrichment analysis identified that immune-related functions were expectedly predominant among the up- or down-regulated genes. The most frequently downregulated genes in significantly altered functional categories were two leukocyte immunoglobulin like receptors LILRB1 (FDR p = 0.005) and LILRB2 (FDR p = 0.027). PCA analysis demonstrated that LILRB1 and LILRB2 expression discriminated all of the Long COVID samples from COVID recovered samples.
Discussion: Downregulation of these inhibitory receptors similarly indicates a sustained pro-inflammatory state in Long COVID PBMCs. LILRB1 and LILRB2 should be validated as prospective biomarkers of Long COVID in larger cohorts, over time and against clinically overlapping conditions.

Keywords:  COVID-19; LILRB1; LILRB2; Long COVID; biomarker; inflammation; transcriptomics

DOI:  https://doi.org/10.3389/fimmu.2024.1450853
Trends Endocrinol Metab. 2024 Dec 17. pii: S1043-2760(24)00298-4. [Epub ahead of print]

Skeletal muscle adaptations and post-exertional malaise in long COVID.

Braeden T Charlton, Richie P Goulding, Richard T Jaspers, Brent Appelman, Michèle van Vugt, Rob C I Wüst.

  When acute SARS-CoV-2 infections cause symptoms that persist longer than 3 months, this condition is termed long COVID. Symptoms experienced by patients often include myalgia, fatigue, brain fog, cognitive impairments, and post-exertional malaise (PEM), which is the worsening of symptoms following mental or physical exertion. There is little consensus on the pathophysiology of exercise-induced PEM and skeletal-muscle-related symptoms. In this opinion article we highlight intrinsic mitochondrial dysfunction, endothelial abnormalities, and a muscle fiber type shift towards a more glycolytic phenotype as main contributors to the reduced exercise capacity in long COVID. The mechanistic trigger for physical exercise to induce PEM is unknown, but rapid skeletal muscle tissue damage and intramuscular infiltration of immune cells contribute to PEM-related symptoms.

Keywords:  long COVID; physical inactivity; post-exertional malaise; skeletal muscle

DOI:  https://doi.org/10.1016/j.tem.2024.11.008