bims-musmir 2024-06-02 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024‒06‒02
twelve papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Loss of HNRNPU in Skeletal Muscle Increases Intramuscular Infiltration of Ly6C Positive Cells, leading to Muscle Atrophy through Activation of NF-κB Signaling.
microRNA-mRNA expression profiles in the skeletal muscle of myotonic dystrophy type 1.
Aging-dependent mitochondrial bioenergetic impairment in the skeletal muscle of NNT-deficient mice.
Studying intramuscular fat deposition and muscle regeneration: insights from a comparative analysis of mouse strains, injury models, and sex differences.
EDA2R-NIK signaling in cancer cachexia.
Unresolved questions in the regulation of skeletal muscle insulin action by reactive oxygen species.
Muscle-specific PGC-1α modulates mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.
Synaptic defects in a drosophila model of muscular dystrophy.
Reduced beta-hydroxybutyrate disposal after ketogenic diet feeding in mice.
Axonal autophagic vesicle transport in the rat optic nerve in vivo under normal conditions and during acute axonal degeneration.
Relationship between skeletal mitochondrial function and digital markers of free-living physical activity in older adults.
Mitochondria-Associated MicroRNAs and Parkinson's Disease.

Adv Biol (Weinh). 2024 May 26. e2400152

Loss of HNRNPU in Skeletal Muscle Increases Intramuscular Infiltration of Ly6C Positive Cells, leading to Muscle Atrophy through Activation of NF-κB Signaling.

Eun-Joo Lee, Julia F Charles, Indranil Sinha, Ronald L Neppl.

  Heterogeneous nuclear ribonucleoprotein U (hnRNPU) is known to play multiple biological roles by regulating transcriptional expression, RNA splicing, RNA stability, and chromatin structure in a tissue-dependent manner. The role of hnRNPU in skeletal muscle development and maintenance has not been previously evaluated. In this study, skeletal muscle specific hnRNPU knock out mice is utilized and evaluated skeletal muscle mass and immune cell infiltration through development. By 4 weeks, muscle-specific hnRNPU knockout mice revealed Ly6C+ monocyte infiltration into skeletal muscle, which preceded muscle atrophy. Canonical NF-kB signaling is activated in a myofiber-autonomous manner with hnRNPU repression. Inducible hnRNPU skeletal muscle knockout mice further demonstrated that deletion of hnRNPU in adulthood is sufficient to cause muscle atrophy, suggesting that hnRNPU's role in muscle maintenance is not during development alone. Treatment with salirasib, to inhibit proliferation of immune cells, prevents muscle atrophy in muscle-specific hnRNPU knock out mice, indicating that immune cell infiltration plays causal role in muscle atrophy of hnRNPU knock out mice. Overall, the findings suggest that loss of hnRNPU triggers muscle inflammation and activates NF-κB signaling in a cell-autonomous manner, culminating in muscle atrophy.

Keywords:  HnRNPU; Ly6C positive monocyte; canonical NF‐κB signaling; intramuscular inflammation; muscle atrophy

DOI:  https://doi.org/10.1002/adbi.202400152
Neurol Res. 2024 Jul;46(7): 613-625

microRNA-mRNA expression profiles in the skeletal muscle of myotonic dystrophy type 1.

Mao Li, Yifan Li, Zhanjun Wang, Fang Cui, Fei Yang, Hongfen Wang, Qiang Shi, Xusheng Huang.

  OBJECTIVES: Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults, yet there are currently no disease-modifying treatments. Disrupted miRNA expressions may lead to dysregulation of target mRNAs and dysfunction involved in DM1 pathogenic mechanism.METHODS: We used microarray platforms to examine the miRNA/mRNA expression profiles in skeletal muscle biopsies derived from DM1 patients and matched controls. Bioinformatics analysis and dual-luciferase reporter assay were conducted to provide insight into miRNA-mRNA regulatory networks altered in DM1.
RESULTS: Twenty-three differentially expressed miRNAs and 135 differentially expressed genes were identified. qPCR confirmed that miR-3201, myogenic factor 5 (MYF5), myogenic differentiation 1 (MYOD1), CUGBP, Elav-like family member 1 (CELF1), and CELF2 were significantly up-regulated, while miR-196a, miR-200c, and miR-146a were significantly down-regulated. Enriched functions and pathways such as multicellular organismal development, RNA splicing, cell differentiation, and spliceosome are relevant to DM1. The miRNA-mRNA interaction network revealed that miR-182, miR-30c-2, and miR-200c were the critical nodes that potentially interacted with hub genes. Luciferase reporter assay confirmed the direct interaction between miR-196a and CELF2.
CONCLUSION: Those results implied that the observed miRNA/mRNA dysregulation could contribute to specific functions and pathways related to DM1 pathogenesis, highlighting the dysfunction of miR-196a and CELF2.

Keywords:  Bioinformatics; luciferase reporter assay; microRNA; microarray analysis; myotonic dystrophy

DOI:  https://doi.org/10.1080/01616412.2024.2339102
Exp Gerontol. 2024 May 25. pii: S0531-5565(24)00107-4. [Epub ahead of print]193 112465

Aging-dependent mitochondrial bioenergetic impairment in the skeletal muscle of NNT-deficient mice.

Claudia D C Navarro, Annelise Francisco, Ericka F D Costa, Ana P Dalla Costa, Marina R Sartori, Paulo F V Bizerra, Andréia R Salgado, Tiago R Figueira, Anibal E Vercesi, Roger F Castilho.

  Overall health relies on features of skeletal muscle that generally decline with age, partly due to mechanisms associated with mitochondrial redox imbalance and bioenergetic dysfunction. Previously, aged mice genetically devoid of the mitochondrial NAD(P)+ transhydrogenase (NNT, encoded by the nicotinamide nucleotide transhydrogenase gene), an enzyme involved in mitochondrial NADPH supply, were shown to exhibit deficits in locomotor behavior. Here, by using young, middle-aged, and older NNT-deficient (Nnt-/-) mice and age-matched controls (Nnt+/+), we aimed to investigate how muscle bioenergetic function and motor performance are affected by NNT expression and aging. Mice were subjected to the wire-hang test to assess locomotor performance, while mitochondrial bioenergetics was evaluated in fiber bundles from the soleus, vastus lateralis and plantaris muscles. An age-related decrease in the average wire-hang score was observed in middle-aged and older Nnt-/- mice compared to age-matched controls. Although respiratory rates in the soleus, vastus lateralis and plantaris muscles did not significantly differ between the genotypes in young mice, the rates of oxygen consumption did decrease in the soleus and vastus lateralis muscles of middle-aged and older Nnt-/- mice. Notably, the soleus, which exhibited the highest NNT expression level, was the muscle most affected by aging, and NNT loss. Additionally, histology of the soleus fibers revealed increased numbers of centralized nuclei in older Nnt-/- mice, indicating abnormal morphology. In summary, our findings suggest that NNT expression deficiency causes locomotor impairments and muscle dysfunction during aging in mice.

Keywords:  Age-related muscle dysfunction; Locomotor impairment; Mitochondrial bioenergetics; NNT deficiency; Nicotinamide nucleotide transhydrogenase; Oxidative stress

DOI:  https://doi.org/10.1016/j.exger.2024.112465
Skelet Muscle. 2024 May 29. 14(1): 12

Studying intramuscular fat deposition and muscle regeneration: insights from a comparative analysis of mouse strains, injury models, and sex differences.

Alessandra M Norris, Kiara E Fierman, Jillian Campbell, Rhea Pitale, Muhammad Shahraj, Daniel Kopinke.

Intramuscular fat (IMAT) infiltration, pathological adipose tissue that accumulates between muscle fibers, is a shared hallmark in a diverse set of diseases including muscular dystrophies and diabetes, spinal cord and rotator cuff injuries, as well as sarcopenia. While the mouse has been an invaluable preclinical model to study skeletal muscle diseases, they are also resistant to IMAT formation. To better understand this pathological feature, an adequate pre-clinical model that recapitulates human disease is necessary. To address this gap, we conducted a comprehensive in-depth comparison between three widely used mouse strains: C57BL/6J, 129S1/SvlmJ and CD1. We evaluated the impact of strain, sex and injury type on IMAT formation, myofiber regeneration and fibrosis. We confirm and extend previous findings that a Glycerol (GLY) injury causes significantly more IMAT and fibrosis compared to Cardiotoxin (CTX). Additionally, females form more IMAT than males after a GLY injury, independent of strain. Of all strains, C57BL/6J mice, both females and males, are the most resistant to IMAT formation. In regard to injury-induced fibrosis, we found that the 129S strain formed the least amount of scar tissue. Surprisingly, C57BL/6J of both sexes demonstrated complete myofiber regeneration, while both CD1 and 129S1/SvlmJ strains still displayed smaller myofibers 21 days post injury. In addition, our data indicate that myofiber regeneration is negatively correlated with IMAT and fibrosis. Combined, our results demonstrate that careful consideration and exploration are needed to determine which injury type, mouse model/strain and sex to utilize as preclinical model especially for modeling IMAT formation.

DOI: https://doi.org/10.1186/s13395-024-00344-4
Curr Opin Support Palliat Care. 2024 May 27.

EDA2R-NIK signaling in cancer cachexia.

Samet Agca, Serkan Kir.

PURPOSE OF REVIEW: Cachexia is a debilitating condition causing weight loss and skeletal muscle wasting that negatively influences treatment and survival of cancer patients. The objective of this review is to describe recent discoveries on the role of a novel signaling pathway involving ectodysplasin A2 receptor (EDA2R) and nuclear factor κB (NFκB)-inducing kinase (NIK) in muscle atrophy.RECENT FINDINGS: Studies identified tumor-induced upregulation of EDA2R expression in muscle tissues in pre-clinical cachexia models and patients with various cancers. Activation of EDA2R by its ligand promoted atrophy in cultured myotubes and muscle tissue, which depended on NIK activity. The non-canonical NFκB pathway via NIK also stimulated muscle atrophy. Mice lacking EDA2R or NIK were protected from muscle loss due to tumors. Tumor-induced cytokine oncostatin M (OSM) upregulated EDA2R expression in muscles whereas OSM receptor-deficient mice were resistant to muscle wasting.
SUMMARY: Recent discoveries revealed a mechanism involving EDA2R-NIK signaling and OSM that drives cancer-associated muscle loss, opening up new directions for designing anti-cachexia treatments. The therapeutic potential of targeting this mechanism to prevent muscle loss should be further investigated. Future research should also explore broader implications of the EDA2R-NIK pathway in other muscle wasting diseases and overall muscle health.

DOI: https://doi.org/10.1097/SPC.0000000000000705
FEBS Lett. 2024 May 27.

Unresolved questions in the regulation of skeletal muscle insulin action by reactive oxygen species.

Samantha Gallero, Kaspar W Persson, Carlos Henríquez-Olguín.

  Reactive oxygen species (ROS) are well-established signaling molecules implicated in a wide range of cellular processes, including both oxidative stress and intracellular redox signaling. In the context of insulin action within its target tissues, ROS have been reported to exert both positive and negative regulatory effects. However, the precise molecular mechanisms underlying this duality remain unclear. This Review examines the complex role of ROS in insulin action, with a particular focus on skeletal muscle. We aim to address three critical aspects: (a) the proposed intracellular pro-oxidative redox shift elicited by insulin, (b) the evidence supporting that redox-sensitive cysteine modifications impact insulin signaling and action, and (c) cellular mechanisms underlying how ROS can paradoxically act as both enhancers and inhibitors of insulin action. This Review underscores the urgent need for more systematic research to identify specific reactive species, redox targets, and the physiological significance of redox signaling in maintaining insulin action and metabolic health, with a particular emphasis on human skeletal muscle.

Keywords:  hydrogen peroxide; insulin action; insulin signaling; metabolism; reactive oxygen species; redox signaling; skeletal muscle

DOI:  https://doi.org/10.1002/1873-3468.14937
Exp Gerontol. 2024 May 28. pii: S0531-5565(24)00110-4. [Epub ahead of print]193 112468

Muscle-specific PGC-1α modulates mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.

Lei Song, Jianfeng Xue, Lingfen Xu, Lin Cheng, Yongxia Zhang, Xiaojun Wang.

  BACKGROUND: Aged sarcopenia is characterized by loss of skeletal muscle mass and strength, and mitochondrial dysregulation in skeletal myocyte is considered as a major factor. Here, we aimed to analyze the effects of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) on mitochondrial reactive oxygen species (ROS) and nuclear factor erythroid 2-related factor 2 (Nrf2) in aged skeletal muscles.METHODS: C2C12 cells were stimulated by 50 μM 7β-hydroxycholesterol (7β-OHC) to observe the changes of cellular ROS, mitochondrial ROS, and expression of PGC-1α and Nrf2. Different PGC-1α expression in cells was established by transfection with small interfering RNA (siRNA) or plasmids overexpressing PGC-1α (pEX-3-PGC-1α). The effects of different PGC-1α expression on cellular ROS, mitochondrial ROS and Nrf2 expression were measured in cells. Wild type (WT) mice and PGC-1α conditional knockout (CKO) mice were used to analyze the effects of PGC-1α on aged sarcopenia and expression of Nrf2 and CD38 in gastrocnemius muscles. Diethylmaleate, a Nrf2 activator, was used to analyze the connection between PGC-1α and Nrf2 in cells and in mice.
RESULTS: In C2C12 cells, the expressions of PGC-1α and Nrf2 were declined by the 7β-OHC treatment or PGC-1α silence. Moreover, PGC-1α silence increased the harmful ROS and decreased the Nrf2 protein expression in the 7β-OHC-treated cells. PGC-1α overexpression decreased the harmful ROS and increased the Nrf2 protein expression in the 7β-OHC-treated cells. Diethylmaleate treatment decreased the harmful ROS in the 7β-OHC-treated or PGC-1α siRNA-transfected cells. At the same age, muscle-specific PGC-1α deficiency aggravated aged sarcopenia, decreased Nrf2 expression and increased CD38 expression in gastrocnemius muscles compared with the WT mice. Diethylmaleate treatment improved the muscle function and decreased the CD38 expression in the old two genotypes.
CONCLUSIONS: Our study demonstrated that PGC-1α modulated mitochondrial oxidative stress in aged sarcopenia through regulating Nrf2.

Keywords:  7β-hydroxycholesterol (7β-OHC); C2C12 cells; CD38; PGC-1α conditional knockout (CKO) mice; PGC-1α siRNA

DOI:  https://doi.org/10.1016/j.exger.2024.112468
Front Cell Neurosci. 2024 ;18 1381112

Synaptic defects in a drosophila model of muscular dystrophy.

Jessica M Sidisky, Alex Winters, Russell Caratenuto, Daniel T Babcock.

  Muscular dystrophies are a devastating class of diseases that result in a progressive loss of muscle integrity. Duchenne Muscular Dystrophy, the most prevalent form of Muscular Dystrophy, is due to the loss of functional Dystrophin. While much is known regarding destruction of muscle tissue in these diseases, much less is known regarding the synaptic defects that also occur in these diseases. Synaptic defects are also among the earliest hallmarks of neurodegenerative diseases, including the neuromuscular disease Amyotrophic Lateral Sclerosis (ALS). Our current study investigates synaptic defects within adult muscle tissues as well as presynaptic motor neurons in Drosophila dystrophin mutants. Here we demonstrate that the progressive, age-dependent loss of flight ability in dystrophin mutants is accompanied by disorganization of Neuromuscular Junctions (NMJs), including impaired localization of both presynaptic and postsynaptic markers. We show that these synaptic defects, including presynaptic defects within motor neurons, are due to the loss of Dystrophin specifically within muscles. These results should help to better understand the early synaptic defects preceding cell loss in neuromuscular disorders.

Keywords:  degeneration; dystrophin; flight; neuromuscular junction; postsynaptic; presynaptic

DOI:  https://doi.org/10.3389/fncel.2024.1381112
bioRxiv. 2024 May 18. pii: 2024.05.16.594369. [Epub ahead of print]

Reduced beta-hydroxybutyrate disposal after ketogenic diet feeding in mice.

Cody M Cousineau, Detrick Snyder, JeAnna R Redd, Sophia Turner, Treyton Carr, Dave Bridges.

The ketogenic diet (KD) has garnered considerable attention due to its potential benefits in weight loss, health improvement, and performance enhancement. However, the phenotypic responses to KD vary widely between individuals. Skeletal muscle is a major contributor to ketone body (KB) catabolism, however, the regulation of ketolysis is not well understood. In this study, we evaluated how mTORC1 activation and a ketogenic diet modify ketone body disposal in muscle Tsc1 knockout (KO) mice, inbred A/J mice, and Diversity Outbred (DO) mice. Muscle Tsc1 KO mice demonstrated enhanced ketone body clearance. Contrary to expectations, KD feeding in A/J mice did not improve KB disposal, and in most strains disposal was reduced. Transcriptional analysis revealed reduced expression of important ketolytic genes in KD-fed A/J mice, suggesting impaired KB catabolism. Diversity Outbred (DO) mice displayed variable responses to KD, with most mice showing worsened KB disposal. Exploratory analysis on these data suggest potential correlations between KB disposal and cholesterol levels as well as weight gain on a KD. Our findings suggest that ketone body disposal may be regulated by both nutritional and genetic factors and these relationships may help explain interindividual variability in responses to ketogenic diets.

DOI: https://doi.org/10.1101/2024.05.16.594369
Acta Neuropathol Commun. 2024 May 29. 12(1): 82

Axonal autophagic vesicle transport in the rat optic nerve in vivo under normal conditions and during acute axonal degeneration.

Xiaoyue Luo, Jiong Zhang, Johan Tolö, Sebastian Kügler, Uwe Michel, Mathias Bähr, Jan Christoph Koch.

  Neurons pose a particular challenge to degradative processes like autophagy due to their long and thin processes. Autophagic vesicles (AVs) are formed at the tip of the axon and transported back to the soma. This transport is essential since the final degradation of the vesicular content occurs only close to or in the soma. Here, we established an in vivo live-imaging model in the rat optic nerve using viral vector mediated LC3-labeling and two-photon-microscopy to analyze axonal transport of AVs. Under basal conditions in vivo, 50% of the AVs are moving with a majority of 85% being transported in the retrograde direction. Transport velocity is higher in the retrograde than in the anterograde direction. A crush lesion of the optic nerve results in a rapid breakdown of retrograde axonal transport while the anterograde transport stays intact over several hours. Close to the lesion site, the formation of AVs is upregulated within the first 6 h after crush, but the clearance of AVs and the levels of lysosomal markers in the adjacent axon are reduced. Expression of p150Glued, an adaptor protein of dynein, is significantly reduced after crush lesion. In vitro, fusion and colocalization of the lysosomal marker cathepsin D with AVs are reduced after axotomy. Taken together, we present here the first in vivo analysis of axonal AV transport in the mammalian CNS using live-imaging. We find that axotomy leads to severe defects of retrograde motility and a decreased clearance of AVs via the lysosomal system.

Keywords:  Autophagy; Axonal transport; Axotomy; Dynactin; Optic nerve; p150Glued

DOI:  https://doi.org/10.1186/s40478-024-01791-2
Geroscience. 2024 May 29.

Relationship between skeletal mitochondrial function and digital markers of free-living physical activity in older adults.

Amal A Wanigatunga, Fangyu Liu, Ryan J Dougherty, Karen Bandeen Roche, Jacek K Urbanek, Marta Zampino, Eleanor M Simonsick, Qu Tian, Jennifer A Schrack, Luigi Ferrucci.

  This study examined the association between in vivo skeletal mitochondrial function and digital free-living physical activity patterns-a measure that summarizes biological, phenotypic, functional, and environmental effects on mobility. Among 459 participants (mean age 68 years; 55% women) in the Baltimore Longitudinal Study of Aging, mitochondrial function was quantified as skeletal muscle oxidative capacity via post-exercise phosphocreatine recovery rate (τPCr) in the vastus lateralis muscle of the left thigh, using 31P magnetic resonance spectroscopy. Accelerometry was collected using a 7-day, 24-h wrist-worn protocol and summarized into activity amount, intensity, endurance, and accumulation patterning metrics. Linear regression, two-part linear and logistic (bout analyses), and linear mixed effects models (time-of-day analyses) were used to estimate associations between τPCr and each physical activity metric. Interactions by age, sex, and gait speed were tested. After covariate adjustment, higher τPCr (or poorer mitochondrial function) was associated with lower activity counts/day (β = - 6593.7, SE = 2406.0; p = 0.006) and activity intensity (- 81.5 counts, SE = 12.9; p < 0.001). For activity intensity, the magnitude of association was greater for men and those with slower gait speed (interaction p < 0.02 for both). Conversely, τPCr was not associated with daily active minutes/day (p = 0.15), activity fragmentation (p = 0.13), or endurance at any bout length (p > 0.05 for all). Time-of-day analyses show participants with high τPCr were less active from 6:00 a.m. to 12:00 a.m. than those with low τPCr. Results indicate that poorer skeletal mitochondrial function is primarily associated with lower engagement in high intensity activities. Our findings help define the connection between laboratory-measured mitochondrial function and real-world physical activity behavior.

Keywords:  Aging; Digital biomarker; Movement; Muscle oxidative capacity; Technology; Wearables

DOI:  https://doi.org/10.1007/s11357-024-01212-1
Neurosci Insights. 2024 ;19 26331055241254846

Mitochondria-Associated MicroRNAs and Parkinson's Disease.

Gayatri Reddy Aaluri, Yashmit Choudhary, Subodh Kumar.

  Parkinson's Disease (PD) occurs as a result of the progressive loss of dopaminergic neurons within the substantia nigra causing motor and non-motor symptoms and has become more prevalent within the last several decades. With mitochondria being essential to cellular survival, mitochondrial dysfunction contributes to the disease progression by increasing neuron loss through (1) insufficient ATP production and (2) reactive oxygen species generation. MicroRNAs (miRNAs) are small molecules located throughout cells that regulate gene expression, particularly mitochondrial function. Through their own dysregulation, miRNAs offset the delicate balance of mitochondrial function by altering or dysregulating the expression of proteins, increasing neuroinflammation, increasing retention of toxic substances, limiting the removal of reactive oxygen species, and preventing mitophagy. Improper mitochondrial function places cells at increased risk of apoptosis, a major concern in individuals with PD due to their reduced number of dopaminergic neurons. This article has identified the 17 most promising mitochondrial associated miRNAs within PD: hsa-miR-4639-5p, miR-376a, miR-205, miR-421, miR-34b/c, miR-150, miR-7, miR-132, miR-17-5p, miR-20a, miR-93, miR-106, miR-181, miR-193b, miR-128, miR-181a, and miR-124-3p. These miRNAs alter mitochondrial function and synaptic energy by impeding normal gene expression when up or downregulated. However, there is limited research regarding mitochondria-localized miRNAs that are typically seen in other diseases. Mitochondria-localized miRNA may have a greater impact on mitochondrial dysfunction due to their proximity. Further research is needed to determine the location of these miRNAs and to better understand their regulatory capabilities on mitochondrial and synaptic function within PD.

Keywords:  Parkinson’s disease; alpha-synuclein; mitochondrial dysfunction; mitochondrial microRNAs

DOI:  https://doi.org/10.1177/26331055241254846