bims-musmir 2024-06-16 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2024–06–16
nine papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Skeletal muscle mitochondrial dysfunction mediated by Pseudomonas aeruginosa quorum-sensing transcription factor MvfR: reversing effects with anti-MvfR and mitochondrial-targeted compounds.
Sex Differences in the Association between Skeletal Muscle Energetics and Perceived Physical Fatigability: The Study of Muscle, Mobility and Aging (SOMMA).
Combinatorial metabolomic and transcriptomic analysis of muscle growth in hybrid striped bass (female white bass Morone chrysops x male striped bass M. saxatilis).
The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.
Muscle fibrosis, NF-κB, and TGF-β are differentially altered in two models of paralysis (Botox vs. Neurectomy).
Resveratrol impinges on retrograde communication without inducing mitochondrial biogenesis in aged rat soleus muscle.
Effects of miR-29c on proliferation and adipogenic differentiation of porcine bone marrow mesenchymal stromal cells.
Type 2 diabetes mellitus related sarcopenia: a type of muscle loss distinct from sarcopenia and disuse muscle atrophy.
Transcriptome sequencing and bioinformatics analysis of gastrocnemius muscle in type 2 diabetes mellitus rats.

mBio. 2024 Jun 11. e0129224

Skeletal muscle mitochondrial dysfunction mediated by Pseudomonas aeruginosa quorum-sensing transcription factor MvfR: reversing effects with anti-MvfR and mitochondrial-targeted compounds.

Shifu Aggarwal, Vijay Singh, Arijit Chakraborty, Sujin Cha, Alexandra Dimitriou, Claire de Crescenzo, Olivia Izikson, Lucy Yu, Roberto Plebani, A Aria Tzika, Laurence G Rahme.

  Sepsis and chronic infections with Pseudomonas aeruginosa, a leading "ESKAPE" bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The actions of this pathogen on skeletal muscle remain poorly understood. In skeletal muscle, mitochondria serve as a crucial energy source, which may be perturbed by infection. Here, using the well-established backburn and infection model of murine P. aeruginosa infection, we deciphered the systemic impact of the quorum-sensing transcription factor MvfR (multiple virulence factor regulator) by interrogating, 5 days post-infection, its effect on mitochondrial-related functions in the gastrocnemius skeletal muscle and the outcome of the pharmacological inhibition of MvfR function and that of the mitochondrial-targeted peptide, Szeto-Schiller 31 (SS-31). Our findings show that the MvfR perturbs adenosine triphosphate generation, oxidative phosphorylation, and antioxidant response, elevates the production of reactive oxygen species, and promotes oxidative damage of mitochondrial DNA in the gastrocnemius muscle of infected mice. These impairments in mitochondrial-related functions were corroborated by the alteration of key mitochondrial proteins involved in electron transport, mitochondrial biogenesis, dynamics and quality control, and mitochondrial uncoupling. Pharmacological inhibition of MvfR using the potent anti-MvfR lead, D88, we developed, or the mitochondrial-targeted peptide SS-31 rescued the MvfR-mediated alterations observed in mice infected with the wild-type strain PA14. Our study provides insights into the actions of MvfR in orchestrating mitochondrial dysfunction in the skeletal murine muscle, and it presents novel therapeutic approaches for optimizing clinical outcomes in affected patients.
IMPORTANCE: Skeletal muscle, pivotal for many functions in the human body, including breathing and protecting internal organs, contains abundant mitochondria essential for maintaining cellular homeostasis during infection. The effect of Pseudomonas aeruginosa (PA) infections on skeletal muscle remains poorly understood. Our study delves into the role of a central quorum-sensing transcription factor, multiple virulence factor regulator (MvfR), that controls the expression of multiple acute and chronic virulence functions that contribute to the pathogenicity of PA. The significance of our study lies in the role of MvfR in the metabolic perturbances linked to mitochondrial functions in skeletal muscle and the effectiveness of the novel MvfR inhibitor and the mitochondrial-targeted peptide SS-31 in alleviating the mitochondrial disturbances caused by PA in skeletal muscle. Inhibiting MvfR or interfering with its effects can be a potential therapeutic strategy to curb PA virulence.

Keywords:  ATP; MvfR; PA14; PqsR; Pseudomonas aeruginosa; ROS; bioenergetics; infection; metabolism; mitochondrial dysfunction; mitochondrion; mitophagy; oxidative phosphorylation; quorum sensing; skeletal muscle

DOI:  https://doi.org/10.1128/mbio.01292-24
medRxiv. 2024 May 27. pii: 2024.05.25.24307934. [Epub ahead of print]

Sex Differences in the Association between Skeletal Muscle Energetics and Perceived Physical Fatigability: The Study of Muscle, Mobility and Aging (SOMMA).

Emma L Gay, Paul M Coen, Stephanie Harrison, Reagan E Garcia, Yujia Susanna Qiao, Bret H Goodpaster, Daniel E Forman, Frederico G S Toledo, Giovanna Distefano, Philip A Kramer, Sofhia V Ramos, Anthony J A Molina, Barbara J Nicklas, Steven R Cummings, Peggy M Cawthon, Russell T Hepple, Anne B Newman, Nancy W Glynn.

Greater perceived physical fatigability and lower skeletal muscle energetics are predictors of mobility decline. Characterizing associations between muscle energetics and perceived fatigability may provide insight into potential targets to prevent mobility decline. We examined associations of in vivo (maximal ATP production, ATPmax) and ex vivo (maximal carbohydrate supported oxidative phosphorylation [max OXPHOS] and maximal fatty acid supported OXPHOS [max FAO OXPHOS]) measures of mitochondrial energetics with two measures of perceived physical fatigability, Pittsburgh Fatigability Scale (PFS, 0-50, higher=greater) and Rating of Perceived Exertion (RPE Fatigability, 6-20, higher=greater) after a slow treadmill walk. Participants from the Study of Muscle, Mobility and Aging (N=873) were 76.3±5.0 years old, 59.2% women, and 85.3% White. Higher muscle energetics (both in vivo and ex vivo ) were associated with lower perceived physical fatigability, all p<0.03. When stratified by sex, higher ATPmax was associated with lower PFS Physical for men only; higher max OXPHOS and max FAO OXPHOS were associated with lower RPE fatigability for both sexes. Higher skeletal muscle energetics were associated with 40-55% lower odds of being in the most (PFS≥25, RPE Fatigability≥12) vs least (PFS 0-4, RPE Fatigability 6-7) severe fatigability strata, all p<0.03. Being a woman was associated with 2-3 times higher odds of being in the most severe fatigability strata when controlling for ATPmax but not the in vivo measures (p<0.05). Better mitochondrial energetics were linked to lower fatigability and less severe fatigability in older adults. Findings imply that improving skeletal muscle energetics may mitigate perceived physical fatigability and prolong healthy aging.

DOI: https://doi.org/10.1101/2024.05.25.24307934
BMC Genomics. 2024 Jun 10. 25(1): 580

Combinatorial metabolomic and transcriptomic analysis of muscle growth in hybrid striped bass (female white bass Morone chrysops x male striped bass M. saxatilis).

Sarah A S Rajab, Linnea K Andersen, Linas W Kenter, David L Berlinsky, Russell J Borski, Andrew S McGinty, Christopher M Ashwell, Peter R Ferket, Harry V Daniels, Benjamin J Reading.

   BACKGROUND: Understanding growth regulatory pathways is important in aquaculture, fisheries, and vertebrate physiology generally. Machine learning pattern recognition and sensitivity analysis were employed to examine metabolomic small molecule profiles and transcriptomic gene expression data generated from liver and white skeletal muscle of hybrid striped bass (white bass Morone chrysops x striped bass M. saxatilis) representative of the top and bottom 10 % by body size of a production cohort.
RESULTS: Larger fish (good-growth) had significantly greater weight, total length, hepatosomatic index, and specific growth rate compared to smaller fish (poor-growth) and also had significantly more muscle fibers of smaller diameter (≤ 20 µm diameter), indicating active hyperplasia. Differences in metabolomic pathways included enhanced energetics (glycolysis, citric acid cycle) and amino acid metabolism in good-growth fish, and enhanced stress, muscle inflammation (cortisol, eicosanoids) and dysfunctional liver cholesterol metabolism in poor-growth fish. The majority of gene transcripts identified as differentially expressed between groups were down-regulated in good-growth fish. Several molecules associated with important growth-regulatory pathways were up-regulated in muscle of fish that grew poorly: growth factors including agt and agtr2 (angiotensins), nicotinic acid (which stimulates growth hormone production), gadd45b, rgl1, zfp36, cebpb, and hmgb1; insulin-like growth factor signaling (igfbp1 and igf1); cytokine signaling (socs3, cxcr4); cell signaling (rgs13, rundc3a), and differentiation (rhou, mmp17, cd22, msi1); mitochondrial uncoupling proteins (ucp3, ucp2); and regulators of lipid metabolism (apoa1, ldlr). Growth factors pttg1, egfr, myc, notch1, and sirt1 were notably up-regulated in muscle of good-growing fish.
CONCLUSION: A combinatorial pathway analysis using metabolomic and transcriptomic data collectively suggested promotion of cell signaling, proliferation, and differentiation in muscle of good-growth fish, whereas muscle inflammation and apoptosis was observed in poor-growth fish, along with elevated cortisol (an anti-inflammatory hormone), perhaps related to muscle wasting, hypertrophy, and inferior growth. These findings provide important biomarkers and mechanisms by which growth is regulated in fishes and other vertebrates as well.

Keywords:  Fish; Genome; Growth; Machine learning; Metabolomics; Striped bass; Transcriptomics

DOI:  https://doi.org/10.1186/s12864-024-10325-y
Nat Commun. 2024 Jun 08. 15(1): 4915

The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.

Joan Serrano, Jordan Boyd, Ian S Brown, Carter Mason, Kathleen R Smith, Katalin Karolyi, Santosh K Maurya, Nishita N Meshram, Vanida Serna, Grace M Link, Stephen J Gardell, George A Kyriazis.

The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health.

DOI: https://doi.org/10.1038/s41467-024-49100-8
Adv Wound Care (New Rochelle). 2024 Jun 15.

Muscle fibrosis, NF-κB, and TGF-β are differentially altered in two models of paralysis (Botox vs. Neurectomy).

James T Redden, Jingyao Deng, David J Cohen, Zvi Schwartz, Michael James McClure.

OBJECTIVE: Volumetric muscle loss (VML) results in intramuscular axotomy, denervating muscle and leading to paralysis and loss of muscle function. Once the nerve is damaged, paralyzed skeletal muscle will atrophy and accumulate non-contractile connective tissue. The objective of this study was to determine differences in connective tissue, atrophy, and inflammatory signaling between two paralysis models, botulinum toxin (Botox), which blocks acetylcholine transmission while keeping nerves intact, and neurectomy, which eliminates all nerve to muscle signaling.
APPROACH: Twenty-eight male Sprague Dawley rats were randomized and received either a sciatic-femoral neurectomy (SFN), Botox-induced muscle paralysis of the proximal femur muscles, quadriceps femoris, hamstrings, and calf muscles (BTX), or sham. Muscle force was measured 52 days post-surgery, and samples were collected for histology, protein, and mRNA assays.
RESULTS: SNF and BTX decreased twitch and tetanic force, decreased fiber size by two-fold, and increased myogenic expression compared to controls. SFN increased levels of all major ECM proteins correlating with fibrosis (e.g. laminin, fibronectin, and collagen type(s) I, III, VI). SFN also increased pro-fibrotic and pro-inflammatory mRNA compared to BTX and controls.
INNOVATION: SFN and BTX were similar in gross morphology and functional deficiencies. However, SFN exhibited a higher amount of fibrosis in histological sections and immunoblotting. The present study shows evidence that nerve signaling changes NF-κB and TGF-β signaling, warranting future studies to determine the mechanisms involved.
CONCLUSION: These data indicate that nerve signaling may influence fibrogenesis following denervation, but the mechanisms involved may differ as a function of the method of paralysis.

DOI: https://doi.org/10.1089/wound.2024.0045
Exp Gerontol. 2024 Jun 12. pii: S0531-5565(24)00127-X. [Epub ahead of print] 112485

Resveratrol impinges on retrograde communication without inducing mitochondrial biogenesis in aged rat soleus muscle.

Rosa Di Lorenzo, Guglielmina Chimienti, Anna Picca, Lucia Trisolini, Tiziana Latronico, Grazia Maria Liuzzi, Vito Pesce, Christiaan Leuweenburgh, Angela Maria Serena Lezza.

  The natural polyphenol resveratrol (RSV) might counteract the skeletal muscle age-related loss of muscle mass and strength/function partly acting on mitochondria. This work analysed the effects of a six-week administration of RSV (50 mg/kg/day) in the oxidative Soleus (Sol) skeletal muscle of old rats (27 months old). RSV effects on key mitochondrial biogenesis proteins led to un unchanged amount of SIRT1 protein and a marked decrease (60 %) in PGC-1α protein. In addition, Peroxyredoxin 3 (PRXIII) protein decreased by 50 %, which on overall suggested the absence of induction of mitochondrial biogenesis by RSV in old Sol. A novel direct correlation between PGC-1α and PRXIII proteins was demonstrated by correlation analysis in RSV and ad-libitum (AL) rats, supporting the reciprocally coordinated expression of the proteins. RSV supplementation led to an unexpected 50 % increase in the frequency of the oxidized base OH8dG in mtDNA. Furthermore, RSV supplementation induced a 50 % increase in the DRP1 protein of mitochondrial dynamics. In both rat groups an inverse correlation between PGC-1α and the frequency of OH8dG as well as an inverse correlation between PRXIII and the frequency of OH8dG were also found, suggestive of a relationship between oxidative damage to mtDNA and mitochondrial biogenesis activity. Such results may indicate that the antioxidant activity of RSV in aged Sol impinged on the oxidative fiber-specific, ROS-mediated, retrograde communication, thereby affecting the expression of SIRT1, PGC-1α and PRXIII, reducing the compensatory responses to the age-related mitochondrial oxidative stress and decline.

Keywords:  Mitochondrial biogenesis; Rat soleus skeletal muscle; Resveratrol

DOI:  https://doi.org/10.1016/j.exger.2024.112485
Adipocyte. 2024 Dec;13(1): 2365211

Effects of miR-29c on proliferation and adipogenic differentiation of porcine bone marrow mesenchymal stromal cells.

Anjing Zhang, Lu Lu, Fuxing Yang, Tingting Luo, Shuqi Yang, Peidong Yang, Xuemin Li, Xiaoli Deng, Yang Qiu, Litong Chen, Keren Long, Dengke Pan, Long Jin, Mingzhou Li, Li Chen.

  microRNAs (miRNAs), a subclass of noncoding short RNAs, direct cells fate decisions that are important for cell proliferation and cell lineage decisions. Adipogenic differentiation contributes greatly to the development of white adipose tissue, involving of highly organized regulation by miRNAs. In the present study, we screened and identified 78 differently expressed miRNAs of porcine BMSCs during adipogenic differentiation. Of which, the role of miR-29c in regulating the proliferation and adipogenic differentiation was proved and detailed. Specifically, over-expression miR-29c inhibits the proliferation and adipogenic differentiation of BMSCs, which were reversed upon miR-29c inhibitor. Interference of IGF1 inhibits the proliferation and adipogenic differentiation of BMSCs. Mechanistically, miR-29c regulates the proliferation and adipogenic differentiation of BMSCs by targeting IGF1 and further regulating the MAPK pathway and the PI3K-AKT-mTOR pathway, respectively. In conclusion, we highlight the important role of miR-29c in regulating proliferation and adipogenic differentiation of BMSCs.

Keywords:  BMSCs; IGF1; adipogenic differentiation; miR-29c; proliferation

DOI:  https://doi.org/10.1080/21623945.2024.2365211
Front Endocrinol (Lausanne). 2024 ;15 1375610

Type 2 diabetes mellitus related sarcopenia: a type of muscle loss distinct from sarcopenia and disuse muscle atrophy.

Zhenchao Liu, Yunliang Guo, Chongwen Zheng.

  Muscle loss is a significant health concern, particularly with the increasing trend of population aging, and sarcopenia has emerged as a common pathological process of muscle loss in the elderly. Currently, there has been significant progress in the research on sarcopenia, including in-depth analysis of the mechanisms underlying sarcopenia caused by aging and the development of corresponding diagnostic criteria, forming a relatively complete system. However, as research on sarcopenia progresses, the concept of secondary sarcopenia has also been proposed. Due to the incomplete understanding of muscle loss caused by chronic diseases, there are various limitations in epidemiological, basic, and clinical research. As a result, a comprehensive concept and diagnostic system have not yet been established, which greatly hinders the prevention and treatment of the disease. This review focuses on Type 2 Diabetes Mellitus (T2DM)-related sarcopenia, comparing its similarities and differences with sarcopenia and disuse muscle atrophy. The review show significant differences between the three muscle-related issues in terms of pathological changes, epidemiology and clinical manifestations, etiology, and preventive and therapeutic strategies. Unlike sarcopenia, T2DM-related sarcopenia is characterized by a reduction in type I fibers, and it differs from disuse muscle atrophy as well. The mechanism involving insulin resistance, inflammatory status, and oxidative stress remains unclear. Therefore, future research should further explore the etiology, disease progression, and prognosis of T2DM-related sarcopenia, and develop targeted diagnostic criteria and effective preventive and therapeutic strategies to better address the muscle-related issues faced by T2DM patients and improve their quality of life and overall health.

Keywords:  disuse muscle atrophy; muscle fibers; muscle loss; sarcopenia; type 2 diabetes mellitus

DOI:  https://doi.org/10.3389/fendo.2024.1375610
BMC Musculoskelet Disord. 2024 Jun 08. 25(1): 457

Transcriptome sequencing and bioinformatics analysis of gastrocnemius muscle in type 2 diabetes mellitus rats.

Kuishuai Xu, Liang Zhang, Tianrui Wang, Tengbo Yu, Xia Zhao, Yingze Zhang.

   OBJECTIVE: Type 2 diabetes mellitus (T2DM) is one of the high risk factors for sarcopenia. However, the pathogenesis of diabetic sarcopenia has not been fully elucidated. This study obtained transcriptome profiles of gastrocnemius muscle in normal and T2DM rats based on high-throughput sequencing technology, which may provide new ideas for exploring the pathogenesis of diabetic sarcopenia.
METHODS: Twelve adult male Sprague-Dawley rats were randomly divided into Control group and T2DM group, and gastrocnemius muscle tissue was retained for transcriptome sequencing and real-time quantitative polymerase chain reaction (qRT-PCR) 6 months later. Screening differentially expressed genes (DEGs), Cluster analysis, gene ontology (GO) functional annotation analysis and Kyoto Encyclopedia of Genes and Gnomes (KEGG) functional annotation and enrichment analysis were performed for DEGs. Six DEGs related to apoptosis were selected for qTR-PCR verification.
RESULTS: Transcriptomic analysis showed that there were 1016 DEGs between the gastrocnemius muscle of T2DM and normal rats, among which 665 DEGs were up-regulated and 351 DEGs were down-regulated. GO analysis showed that the extracellular matrix organization was the most enriched in biological processes, with 26 DEGs. The extracellular matrix with 35 DEGs was the most abundant cellular component. The extracellular matrix structural constituent, with 26 DEGs, was the most enriched in molecular functions. The highest number of DEGs enriched in biological processes, cellular components and molecular functions were positive regulation of transcription by RNA polymerase II, nucleus and metal ion binding, respectively. There were 78, 230 and 89 DEGs respectively. KEGG pathway enrichment analysis showed that ECM-receptor interaction, PI3K-Akt signaling pathway and TGF-β signaling pathway(p < 0.001) had higher enrichment degree and number of DEGs. qRT-PCR results showed that the fold change of Map3k14, Atf4, Pik3r1, Il3ra, Gadd45b and Bid were 1.95, 3.25, 2.97, 2.38, 0.43 and 3.6, respectively. The fold change of transcriptome sequencing were 3.45, 2.21, 2.59, 5.39, 0.49 and 2.78, respectively. The transcriptional trends obtained by qRT-PCR were consistent with those obtained by transcriptome sequencing.
CONCLUSIONS: Transcriptomic analysis was used to obtain the "gene profiles" of gastrocnemius muscle of T2DM and normal rats. qRT-PCR verification showed that the genes related to apoptosis were differentially expressed. These DEGs and enrichment pathways may provide new ideas for exploring the pathogenesis of diabetic sarcopenia.

Keywords:  Apoptosis; Gastrocnemius muscle; Sarcopenia; Transcriptomics; Type 2 diabetes mellitus

DOI:  https://doi.org/10.1186/s12891-024-07568-x