bims-musmir 2024-12-01 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024–12–01
eleven papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

miR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemia.
SMN Deficiency Induces an Early Non-Atrophic Myopathy with Alterations in the Contractile and Excitatory Coupling Machinery of Skeletal Myofibers in the SMN∆7 Mouse Model of Spinal Muscular Atrophy.
Upregulated miR-10b-5p as a potential miRNA signature in amyotrophic lateral sclerosis patients.
The AMPK allosteric activator MK-8722 improves the histology and spliceopathy in myotonic dystrophy type 1 (DM1) skeletal muscle.
Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle.
A rare genetic variant in APEX1 is associated with familial amyotrophic lateral sclerosis with slow progression.
Overexpression of enhanced yellow fluorescent protein fused with Channelrhodopsin-2 causes contractile dysfunction in skeletal muscle.
Potential Vitamin E Signaling Mediators in Skeletal Muscle.
Sex differences in skeletal muscle metabolism in exercise and type 2 diabetes mellitus.
Endurance Exercise Training Alters Lipidomic Profiles of Plasma and Eight Tissues in Rats: a MoTrPAC study.
A panoramic view of cell population dynamics in mammalian aging.

Sci Rep. 2024 11 26. 14(1): 29393

miR-1, miR-133a, miR-29b and skeletal muscle fibrosis in chronic limb-threatening ischaemia.

Alan J Keane, Clara Sanz-Nogués, Dulan Jayasooriya, Michael Creane, Xizhe Chen, Caomhán J Lyons, Isha Sikri, Katarzyna Goljanek-Whysall, Timothy O'Brien.

  Chronic limb-threatening ischaemia (CLTI), the most severe manifestation of peripheral arterial disease (PAD), is associated with a poor prognosis and high amputation rates. Despite novel therapeutic approaches being investigated, no significant clinical benefits have been observed yet. Understanding the molecular pathways of skeletal muscle dysfunction in CLTI is crucial for designing successful treatments. This study aimed to identify miRNAs dysregulated in muscle biopsies from PAD cohorts. Using MIcroRNA ENrichment TURned NETwork (MIENTURNET) on a publicly accessible RNA-sequencing dataset of PAD cohorts, we identified a list of miRNAs that were over-represented among the upregulated differentially expressed genes (DEGs) in CLTI. Next, we validated the altered expression of these miRNAs and their targets in mice with hindlimb ischaemia (HLI). Our results showed a significant downregulation of miR-1, miR-133a, and miR-29b levels in the ischaemic limbs versus the contralateral non-ischaemic limb. A miRNA target protein-protein interaction network identified extracellular matrix components, including collagen-1a1, -3a1, and -4a1, fibronectin-1, fibrin-1, matrix metalloproteinase-2 and -14, and Sparc, which were upregulated in the ischaemic muscle of mice. This is the first study to identify miR-1, miR-133a, and miR-29b as potential contributors to fibrosis and vascular pathology in CLTI muscle, which supports their potential as novel therapeutic agents for this condition.

Keywords:  Chronic limb-threatening ischaemia; Fibrosis; MicroRNAs; Muscle regeneration

DOI:  https://doi.org/10.1038/s41598-024-76415-9
Int J Mol Sci. 2024 Nov 19. pii: 12415. [Epub ahead of print]25(22):

SMN Deficiency Induces an Early Non-Atrophic Myopathy with Alterations in the Contractile and Excitatory Coupling Machinery of Skeletal Myofibers in the SMN∆7 Mouse Model of Spinal Muscular Atrophy.

María T Berciano, Alaó Gatius, Alba Puente-Bedia, Alexis Rufino-Gómez, Olga Tarabal, José C Rodríguez-Rey, Jordi Calderó, Miguel Lafarga, Olga Tapia.

  Spinal muscular atrophy (SMA) is caused by a deficiency of the ubiquitously expressed survival motor neuron (SMN) protein. The main pathological hallmark of SMA is the degeneration of lower motor neurons (MNs) with subsequent denervation and atrophy of skeletal muscle. However, increasing evidence indicates that low SMN levels not only are detrimental to the central nervous system (CNS) but also directly affect other peripheral tissues and organs, including skeletal muscle. To better understand the potential primary impact of SMN deficiency in muscle, we explored the cellular, ultrastructural, and molecular basis of SMA myopathy in the SMNΔ7 mouse model of severe SMA at an early postnatal period (P0-7) prior to muscle denervation and MN loss (preneurodegenerative [PND] stage). This period contrasts with the neurodegenerative (ND) stage (P8-14), in which MN loss and muscle atrophy occur. At the PND stage, we found that SMN∆7 mice displayed early signs of motor dysfunction with overt myofiber alterations in the absence of atrophy. We provide essential new ultrastructural data on focal and segmental lesions in the myofibrillar contractile apparatus. These lesions were observed in association with specific myonuclear domains and included abnormal accumulations of actin-thin myofilaments, sarcomere disruption, and the formation of minisarcomeres. The sarcoplasmic reticulum and triads also exhibited ultrastructural alterations, suggesting decoupling during the excitation-contraction process. Finally, changes in intermyofibrillar mitochondrial organization and dynamics, indicative of mitochondrial biogenesis overactivation, were also found. Overall, our results demonstrated that SMN deficiency induces early and MN loss-independent alterations in myofibers that essentially contribute to SMA myopathy. This strongly supports the growing body of evidence indicating the existence of intrinsic alterations in the skeletal muscle in SMA and further reinforces the relevance of this peripheral tissue as a key therapeutic target for the disease.

Keywords:  SMA; SMN∆7 mice; actin filaments; mitochondria; sarcomere; skeletal muscle; triads

DOI:  https://doi.org/10.3390/ijms252212415
Front Cell Neurosci. 2024 ;18 1457704

Upregulated miR-10b-5p as a potential miRNA signature in amyotrophic lateral sclerosis patients.

Banaja P Dash, Axel Freischmidt, Anika M Helferich, Albert C Ludolph, Peter M Andersen, Jochen H Weishaupt, Andreas Hermann.

  Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset disease marked by a progressive degeneration of motor neurons (MNs) present in the spinal cord, brain stem and motor cortex. Death in most patients usually occurs within 2-4 years after symptoms onset. Despite promising progress in delineating underlying mechanisms, such as disturbed proteostasis, DNA/RNA metabolism, splicing or proper nucleocytoplasmic shuttling, there are no effective therapies for the vast majority of cases. A reason for this might be the disease heterogeneity and lack of substantial clinical and molecular biomarkers. The identification and validation of such pathophysiology driven biomarkers could be useful for early diagnosis and treatment stratification. Recent advances in next generation RNA-sequencing approaches have provided important insights to identify key changes of non-coding RNAs (ncRNAs) implicated with ALS disease. Especially, microRNAs (miRNAs) have emerged as key post-transcriptional regulators of gene expression to target several genes/pathways by degrading messenger RNAs (mRNAs) or repressing levels of gene expression. In this study, we expand our previous work to identify top-regulated differentially expressed (DE)-miRNAs by combining different normalizations to search for important and generalisable pathomechanistic dysregulations in ALS as putative novel biomarkers of the disease. For this we performed a consensus pipeline of existing datasets to investigate the transcriptomic profile (mRNAs and miRNAs) of MN cell lines from iPSC-derived SOD1- and TARDBP (TDP-43 protein)-mutant-ALS patients and healthy controls to identify potential signatures and their related pathways associated with neurodegeneration. Transcriptional profiling of miRNA-mRNA interactions from MN cell lines in ALS patients revealed differential expression of genes showed greater vulnerability to KEAP1-NRF2 stress response pathway, sharing a common molecular denominator linked to both disease conditions. We also reported that mutations in above genes led to significant upregulation of the top candidate miR-10b-5p, which we could validate in immortalized lymphoblast cell lines (LCLs) derived from sporadic and familial ALS patients and postmortem tissues of familial ALS patients. Collectively, our findings suggest that miRNA analysis simultaneously performed in various human biological samples may reveal shared miRNA profiles potentially useful as a biomarker of the disease.

Keywords:  amyotrophic lateral sclerosis; differentially expressed; human induced pluripotent stem cells; microRNA; motor neurons; next generation RNA sequencing

DOI:  https://doi.org/10.3389/fncel.2024.1457704
FASEB J. 2024 Dec 15. 38(23): e70199

The AMPK allosteric activator MK-8722 improves the histology and spliceopathy in myotonic dystrophy type 1 (DM1) skeletal muscle.

Aymeric Ravel-Chapuis, Chimène Fahmi, Jonathan Gobin, Bernard J Jasmin.

  Multiple signaling pathways have been reported to be altered in Myotonic Dystrophy type 1 (DM1) skeletal muscle, contributing to pathogenicity. In particular, previous work established that AMPK signaling, a key sensor of energy metabolism, is repressed in DM1 mouse muscle and that activating AMPK through exercise and/or with pharmacological activators is beneficial for the DM1 muscle phenotype. Here, we explored the effects of a newer, more specific allosteric AMPK activator acting directly on AMPK. We treated male and female HSALR mice for 1 and 4 weeks with a daily injection of the allosteric activator MK-8722, the AMP mimetic AICAR, or vehicle. Our results show that 1 and 4 weeks of treatment with MK-8722 improves alternative splicing toward wild-type levels in male and female HSALR muscle. However, the effects of MK-8722 were more modest compared to AICAR. In contrast, 4 weeks of treatment with MK-8722 improved muscle histology to a greater extent than AICAR. As expected with AMPK activation, 4 weeks of treatment with MK-8722 and AICAR promoted the expression of slower, more oxidative fibers. Finally, acute injections of MK-8722 and AICAR triggered the rapid and transient increase in phospho-AMPK in muscle. However, the peak of AMPK phosphorylation was lower with MK-8722 compared to AICAR, thereby explaining the more modest effects of AMPK allosteric activation. Altogether, our data demonstrate that chronic activation of AMPK with specific pharmacological activators is beneficial for the DM1 muscle. They further indicate that at least a portion of the beneficial effects seen following the administration of these drugs occurs through AMPK.

Keywords:  AICAR; AMPK; MK‐8722; ZLN‐024; allosteric activator; alternative splicing; myotonic dystrophy type 1; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202401145RR
bioRxiv. 2024 Nov 15. pii: 2024.11.13.623431. [Epub ahead of print]

Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle.

Ran Hee Choi, Takuya Karasawa, Cesar A Meza, J Alan Maschek, Allison Manuel, Linda S Nikolova, Kelsey H Fisher-Wellmen, James E Cox, Amandine Chaix, Katsuhiko Funai.

Objective: Glucagon-like peptide 1 receptor agonists (e.g. semaglutide) potently induce weight loss and thereby reducing obesity-related complications. However, weight regain occurs when treatment is discontinued. An increase in skeletal muscle oxidative phosphorylation (OXPHOS) efficiency upon diet-mediated weight loss has been described, which may contribute to reduced systemic energy expenditure and weight regain. We set out to determine the unknown effect of semaglutide on muscle OXPHOS efficiency.
Methods: C57BL/6J mice were fed a high-fat diet for 12 weeks before receiving semaglutide or vehicle for 1 or 3 weeks. The rate of ATP production and O 2 consumption were measured by a high-resolution respirometry and fluorometry to determine OXPHOS efficiency in skeletal muscle at these 2 timepoints.
Results: Semaglutide treatment led to significant reductions in fat and lean mass. Semaglutide improved skeletal muscle OXPHOS efficiency, measured as ATP produced per O 2 consumed (P/O) in permeabilized muscle fibers. Mitochondrial proteomic analysis revealed changes restricted to two proteins linked to complex III assembly (Lyrm7 and Ttc1, p <0.05 without multiple corrections) without substantial changes in the abundance of OXPHOS subunits.
Conclusions: These data indicate that weight loss with semaglutide treatment increases skeletal muscle mitochondrial efficiency. Future studies could test whether it contributes to weight regain.

DOI: https://doi.org/10.1101/2024.11.13.623431
Acta Neurol Belg. 2024 Nov 28.

A rare genetic variant in APEX1 is associated with familial amyotrophic lateral sclerosis with slow progression.

Yuxin Mi, Peipei Zhang, Xiaotong Hou, Yuqi Ding, Yiying Wang, Hongwu Du, Min Deng.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons and progressive muscle weakness. We aimed to identify the pathogenic genetic variants in familial ALS (fALS) pedigrees and to elucidate their impact on the disease phenotype. Through the analysis of whole-genome sequencing data of 34 fALS probands that screened negative for mutations in the most common ALS-causing genes, we identified a rare missense variant in APEX1 (NM_001641.4: c.22G > A, p.Gly8Arg) associated with ALS in one pedigree. Fluorescence microscopy images using green fluorescent protein (GFP)-fusion proteins suggested that this amino acid substitution could cause an impairment in nuclear localization of the protein. We described the clinical characteristics of this cohort analyzed and found that patients carrying this variant exhibit lower motor neuron onset and prolonged survival. The relation between APEX1 and ALS occurrence has been elusive despite evidence of a neuroprotective role for the gene. This study provides evidence linking an APEX1 variant with fALS and information on the distinct clinical manifestation. This study contributes to the understanding of the genetic basis of ALS, as well as a potential mechanism leading to loss of neurons, highlighting possible opportunities of targeted treatment harnessing the DNA repair process or ameliorating the oxidative stress.

Keywords:  APEX1; Amyotrophic lateral sclerosis; DNA repair; Single nucleotide variant; Whole genome sequencing

DOI:  https://doi.org/10.1007/s13760-024-02692-w
FASEB J. 2024 Nov 30. 38(22): e70185

Overexpression of enhanced yellow fluorescent protein fused with Channelrhodopsin-2 causes contractile dysfunction in skeletal muscle.

Syeda N Lamia, Carol S Davis, Peter C D Macpherson, T Brad Willingham, Yingfan Zhang, Chengyu Liu, Leanne Iannucci, Elahe Ganji, Desmond Harden, Iman Bhattacharya, Adam C Abraham, Susan V Brooks, Brian Glancy, Megan L Killian.

  Skeletal muscle activation using optogenetics has emerged as a promising technique for inducing noninvasive muscle contraction and assessing muscle function both in vivo and in vitro. Transgenic mice overexpressing the optogenetic fusion protein, Channelrhodopsin 2-EYFP (ChR2-EYFP) in skeletal muscle are widely used; however, overexpression of fluorescent proteins can negatively impact the functionality of activable tissues. In this study, we characterized the contractile properties of ChR2-EYFP skeletal muscle and introduced the ChR2-only mouse model that expresses light-responsive ChR2 without the fluorescent EYFP in their skeletal muscles. We found a significant reduction in the contractile ability of ChR2-EYFP muscles compared with ChR2-only and WT mice, observed under both electrical and optogenetic stimulation paradigms. Bulk RNAseq identified the downregulation of genes associated with transmembrane transport and metabolism in ChR2-EYFP muscle, while the ChR2-only muscle did not demonstrate any notable deviations from WT muscle. The RNAseq results were further corroborated by a reduced protein-level expression of ion channel-related HCN2 in ChR2-EYFP muscles and gluconeogenesis-modulating FBP2 in both ChR2-EYFP and ChR2-only muscles. Overall, this study reveals an intrinsic skeletal dysfunction in the widely used ChR2-EYFP mice model and underscores the importance of considering alternative optogenetic models, such as the ChR2-only, for future research in skeletal muscle optogenetics.

Keywords:  Channelrhodopsin‐2; function; optogenetics; skeletal muscle; structure

DOI:  https://doi.org/10.1096/fj.202401664RR
Antioxidants (Basel). 2024 Nov 13. pii: 1383. [Epub ahead of print]13(11):

Potential Vitamin E Signaling Mediators in Skeletal Muscle.

Elisabetta Meacci, Antony Chirco, Mercedes Garcia-Gil.

  Vitamin E (Vit E) deficiency studies underline the relevance of this vitamin in skeletal muscle (SkM) homeostasis. The knowledge of the effectors and modulators of Vit E action in SkM cells is limited, especially in aging and chronic diseases characterized by a decline in musculoskeletal health. Vit E comprises eight fat-soluble compounds grouped into tocopherols and tocotrienols, which share the basic chemical structure but show different biological properties and potentials to prevent diseases. Vit E has antioxidant and non-antioxidant activities and both favorable and adverse effects depending on the specific conditions and tissues. In this review, we focus on the actual knowledge of Vit E forms in SkM functions and new potential signaling effectors (i.e., bioactive sphingolipids and myokines). The possible advantages of Vit E supplementation in counteracting SkM dysfunctions in sarcopenia and under microgravity will also be discussed.

Keywords:  antioxidant action; microgravity; myokines; sarcopenia; skeletal muscle; sphingolipids; vitamin E

DOI:  https://doi.org/10.3390/antiox13111383
Nat Rev Endocrinol. 2024 Nov 27.

Sex differences in skeletal muscle metabolism in exercise and type 2 diabetes mellitus.

Kirstin MacGregor, Stian Ellefsen, Nicolas J Pillon, Daniel Hammarström, Anna Krook.

This Review focuses on currently available literature describing sex differences in skeletal muscle metabolism in humans, as well as highlighting current research gaps within the field. These discussions serve as a call for action to address the current lack of sufficient sex-balanced studies in skeletal muscle research, and the resulting limitations in understanding sex-specific physiological and pathophysiological responses. Although the participation of women in studies has increased, parity between the sexes remains elusive, affecting the validity of conclusions drawn from studies with limited numbers of participants. Changes in skeletal muscle metabolism contribute to the development of metabolic disease (such as type 2 diabetes mellitus), and maintenance of skeletal muscle mass is a key component for health and the ability to maintain an independent life during ageing. Exercise is an important factor in maintaining skeletal muscle health and insulin sensitivity, and offers promise for both prevention and treatment of metabolic disease. With the increased realization of the promise of precision medicine comes the need to increase patient stratification and improve the understanding of responses in different populations. In this context, a better understanding of sex-dependent differences in skeletal muscle metabolism is essential.

DOI: https://doi.org/10.1038/s41574-024-01058-9
Res Sq. 2024 Nov 21. pii: rs.3.rs-5263273. [Epub ahead of print]

Endurance Exercise Training Alters Lipidomic Profiles of Plasma and Eight Tissues in Rats: a MoTrPAC study.

Eric Ortlund, Zhenxin Hou, Chih-Yu Chen, David Gaul, Tiantian Zhang, Samuel Moore, Xueyun Liu, Anna Ivanova, Kristal Maner-Smith, Christopher Newgard, Sue Bodine, Evan Savage, Alexis Bennett, Facundo Fernandez.

Endurance exercise training (ExT) induces metabolic, structural, and functional adaptations via lipidomic modifications, yet the systematic elucidation of lipidome alterations in response to ExT remains incomplete. As a part of the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we leveraged non-targeted and targeted lipidomics for the systematic discovery of lipid alterations in the brown adipose tissue, heart, hippocampus, kidney, liver, lung, skeletal muscle gastrocnemius, subcutaneous white adipose tissue, and plasma in response to 1, 2, 4 or 8 weeks of ExT in 6-month-old male and female Fischer-344 rats. This study demonstrates that these tissues, each with distinct lipidomic features, underwent dynamic, sexually dimorphic lipid remodeling. Exercise trained animals showed reduced whole-body adiposity and improved cardiorespiratory fitness, along with enhanced utilization of lipid stores and dynamic triacylglycerol remodeling compared to sedentary controls in all tissues except hippocampus. They also showed modifications in phospholipids, lysophospholipids, oxylipins, and ceramides in several tissues. Coordinated changes across tissues reflect systemic tissue communication, with liver-plasma-heart connection potentially playing a key role in systemic lipid metabolism during ExT. These data will improve our understanding of lipid-associated biological processes underlying the health-promoting benefits of ExT.

DOI: https://doi.org/10.21203/rs.3.rs-5263273/v1
Science. 2024 Nov 28. eadn3949

A panoramic view of cell population dynamics in mammalian aging.

Zehao Zhang, Chloe Schaefer, Weirong Jiang, Ziyu Lu, Jasper Lee, Andras Sziraki, Abdulraouf Abdulraouf, Brittney Wick, Maximilian Haeussler, Zhuoyan Li, Gesmira Molla, Rahul Satija, Wei Zhou, Junyue Cao.

To elucidate aging-associated cellular population dynamics, we present PanSci, a single-cell transcriptome atlas profiling over 20 million cells from 623 mouse tissues across different life stages, sexes, and genotypes. This comprehensive dataset reveals more than 3,000 unique cellular states and over 200 aging-associated cell populations. Our panoramic analysis uncovered organ-, lineage-, and sex-specific shifts of cellular dynamics during lifespan progression. Moreover, we identify both systematic and organ-specific alterations in immune cell populations associated with aging. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte dependent. Our "cell-omics" strategy enhances comprehension of cellular aging and lays the groundwork for exploring the complex cellular regulatory networks in aging and aging-associated diseases.

DOI: https://doi.org/10.1126/science.adn3949