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Theranostics 2020: Peripheral nerve injury is common in clinic, which leads to severe atrophy and dysfunction of the denervated muscles, but the underlying mechanism is not fully...
: Peripheral nerve injury is common in clinic, which leads to severe atrophy and dysfunction of the denervated muscles, but the underlying mechanism is not fully understood. Recent studies advanced the causative role of mitochondrial dysfunction in muscle atrophy, while the upstream triggers remained unclear. : In the present study, Atrophy of gastrocnemius and tibialis anterior (TA) were evaluated in mice sciatic nerve transection model. Transmission electron microscopy (TEM) was then used to observe the microstructure of atrophic gastrocnemius and mitochondria. Subsequently, small RNA sequencing, luciferase reporter assay and Electrophoretic Mobility Shift (EMSA) were performed to explore the potential signaling pathway involved in skeletal muscle atrophy. The effects of the corresponding pathway on mitochondrial function, mitophagy, apoptosis and muscle atrophy were further determined in C2C12 cells and denervated gastrocnemius. : Gastrocnemius and TA atrophied rapidly after denervation. Obvious decrease of mitochondria number and activation of mitophagy was further observed in atrophic gastrocnemius. Further, miR-142a-5p/ mitofusin-1 (MFN1) axis was confirmed to be activated in denervated gastrocnemius, which disrupted the tubular mitochondrial network, and induced mitochondrial dysfunction, mitophagy and apoptosis. Furthermore, the atrophy of gastrocnemius induced by denervation was relieved through targeting miR-142a-5p/MFN1 axis. : Collectively, our data revealed that miR-142a-5p was able to function as an important regulator of denervation-induced skeletal muscle atrophy by inducing mitochondrial dysfunction, mitophagy, and apoptosis via targeting MFN1. Our findings provide new insights into the mechanism of skeletal muscle atrophy following denervation and propose a viable target for therapeutic intervention in individuals suffering from muscle atrophy after peripheral nerve injury.
Topics: Animals; Apoptosis; Cell Line; Denervation; GTP Phosphohydrolases; Male; Mice; Mice, Inbred C57BL; MicroRNAs; Mitochondria; Mitophagy; Muscle Denervation; Muscle, Skeletal; Muscular Atrophy; Myoblasts; Sciatic Nerve
PubMed: 31938072
DOI: 10.7150/thno.40857 -
Journal of Cachexia, Sarcopenia and... Aug 2022Skeletal muscle exhibits remarkable plasticity under both physiological and pathological conditions. One major manifestation of this plasticity is muscle atrophy that is...
BACKGROUND
Skeletal muscle exhibits remarkable plasticity under both physiological and pathological conditions. One major manifestation of this plasticity is muscle atrophy that is an adaptive response to catabolic stimuli. Because the heterogeneous transcriptome responses to catabolism in different types of muscle cells are not fully characterized, we applied single-nucleus RNA sequencing (snRNA-seq) to unveil muscle atrophy related transcriptional changes at single nucleus resolution.
METHODS
Using a sciatic denervation mouse model of muscle atrophy, snRNA-seq was performed to generate single-nucleus transcriptional profiles of the gastrocnemius muscle from normal and denervated mice. Various bioinformatics analyses, including unsupervised clustering, functional enrichment analysis, trajectory analysis, regulon inference, metabolic signature characterization and cell-cell communication prediction, were applied to illustrate the transcriptome changes of the individual cell types.
RESULTS
A total of 29 539 muscle nuclei (normal vs. denervation: 15 739 vs. 13 800) were classified into 13 nuclear types according to the known cell markers. Among these, the type IIb myonuclei were further divided into two subgroups, which we designated as type IIb1 and type IIb2 myonuclei. In response to denervation, the proportion of type IIb2 myonuclei increased sharply (78.12% vs. 38.45%, P < 0.05). Concomitantly, trajectory analysis revealed that denervated type IIb2 myonuclei clearly deviated away from the normal type IIb2 myonuclei, indicating that this subgroup underwent robust transcriptional reprogramming upon denervation. Signature genes in denervated type IIb2 myonuclei included Runx1, Gadd45a, Igfn1, Robo2, Dlg2, and Sh3d19 (P < 0.001). The gene regulatory network analysis captured a group of atrophy-related regulons (Foxo3, Runx1, Elk4, and Bhlhe40) whose activities were enhanced (P < 0.01), especially in the type IIb2 myonuclei. The metabolic landscape in the myonuclei showed that most of the metabolic pathways were down-regulated by denervation (P < 0.001), while some of the metabolic signalling, such as glutathione metabolism, was specifically activated in the denervated type IIb2 myonulei. We also investigated the transcriptomic alterations in the type I myofibres, muscle stem cells, fibro-adipogenic progenitors, macrophages, endothelial cells and pericytes and characterized their signature responses to denervation. By predicting the cell-cell interactions, we observed that the communications between myofibres and muscle resident cells were diminished by denervation.
CONCLUSIONS
Our results define the myonuclear transition, metabolic remodelling, and gene regulation networks reprogramming associated with denervation-induced muscle atrophy and illustrate the molecular basis of the heterogeneity and plasticity of muscle cells in response to catabolism. These results provide a useful resource for exploring the molecular mechanism of muscle atrophy.
Topics: Animals; Denervation; Endothelial Cells; Mice; Muscle, Skeletal; Muscular Atrophy; RNA, Small Nuclear; Transcriptome
PubMed: 35726356
DOI: 10.1002/jcsm.13023 -
Journal of the American College of... Nov 2022
Topics: Humans; Kidney; Sympathectomy; Hypertension; Denervation; Blood Pressure; Antihypertensive Agents
PubMed: 36357088
DOI: 10.1016/j.jacc.2022.09.025 -
Science Translational Medicine Oct 2023To date, there are no approved treatments for the diminished strength and paralysis that result from the loss of peripheral nerve function due to trauma, heritable...
To date, there are no approved treatments for the diminished strength and paralysis that result from the loss of peripheral nerve function due to trauma, heritable neuromuscular diseases, or aging. Here, we showed that denervation resulting from transection of the sciatic nerve triggered a marked increase in the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in skeletal muscle in mice, providing evidence that injury drives early expression of this aging-associated enzyme or gerozyme. Treating mice with a small-molecule inhibitor of 15-PGDH promoted regeneration of motor axons and formation of neuromuscular synapses leading to an acceleration in recovery of force after an acute nerve crush injury. In aged mice with chronic denervation of muscles, treatment with the 15-PGDH inhibitor increased motor neuron viability and restored neuromuscular junctions and function. These presynaptic changes synergized with previously reported muscle tissue remodeling to result in a marked increase in the strength of aged muscles. We further found that 15-PGDH aggregates defined the target fibers that are histopathologic hallmarks of human neurogenic myopathies, suggesting that the gerozyme may be involved in their etiology. Our data suggest that inhibition of 15-PGDH may constitute a therapeutic strategy to physiologically boost prostaglandin E2, restore neuromuscular connectivity, and promote recovery of strength after acute or chronic denervation due to injury, disease, or aging.
Topics: Mice; Animals; Humans; Aged; Synapses; Hydroxyprostaglandin Dehydrogenases; Prostaglandins; Muscle, Skeletal; Denervation; Nerve Regeneration
PubMed: 37820010
DOI: 10.1126/scitranslmed.adg1485 -
Redox Biology Nov 2022Loss of innervation is a key driver of age associated muscle atrophy and weakness (sarcopenia). Our laboratory has previously shown that denervation induced atrophy is...
Loss of innervation is a key driver of age associated muscle atrophy and weakness (sarcopenia). Our laboratory has previously shown that denervation induced atrophy is associated with the generation of mitochondrial hydroperoxides and lipid mediators produced downstream of cPLA and 12/15 lipoxygenase (12/15-LOX). To define the pathological impact of lipid hydroperoxides generated in denervation-induced atrophy in vivo, we treated mice with liproxstatin-1, a lipid hydroperoxide scavenger. We treated adult male mice with 5 mg/kg liproxstain-1 or vehicle one day prior to sciatic nerve transection and daily for 7 days post-denervation before tissue analysis. Liproxstatin-1 treatment protected gastrocnemius mass and fiber cross sectional area (∼40% less atrophy post-denervation in treated versus untreated mice). Mitochondrial hydroperoxide generation was reduced 80% in vitro and by over 65% in vivo by liproxstatin-1 treatment in denervated permeabilized muscle fibers and decreased the content of 4-HNE by ∼25% post-denervation. Lipidomic analysis revealed detectable levels of 25 oxylipins in denervated gastrocnemius muscle and significantly increased levels for eight oxylipins that are generated by metabolism of fatty acids through 12/15-LOX. Liproxstatin-1 treatment reduced the level of three of the eight denervation-induced oxylipins, specifically 15-HEPE, 13-HOTrE and 17-HDOHE. Denervation elevated protein degradation rates in muscle and treatment with liproxstatin-1 reduced rates of protein breakdown in denervated muscle. In contrast, protein synthesis rates were unchanged by denervation. Targeted proteomics revealed a number of proteins with altered expression after denervation but no effect of liproxstain-1. Transcriptomic analysis revealed 203 differentially expressed genes in denervated muscle from vehicle or liproxstatin-1 treated mice, including ER stress, nitric oxide signaling, Gαi signaling, glucocorticoid receptor signaling, and other pathways. Overall, these data suggest lipid hydroperoxides and oxylipins are key drivers of increased protein breakdown and muscle loss associated with denervation induced atrophy and a potential target for sarcopenia intervention.
Topics: Male; Mice; Animals; Lipid Peroxides; Oxylipins; Sarcopenia; Muscular Atrophy; Muscle, Skeletal; Protein Biosynthesis; Denervation
PubMed: 36283174
DOI: 10.1016/j.redox.2022.102518 -
European Journal of Heart Failure Jun 2014Renal denervation has been developed in order to lower systolic blood pressure in resistant hypertension by a reduction in renal afferent and efferent sympathetic nerve... (Review)
Review
Renal denervation has been developed in order to lower systolic blood pressure in resistant hypertension by a reduction in renal afferent and efferent sympathetic nerve activity. In heart failure sympathetic activation, in particular, renal norepinephrine release is closely associated with morbidity and mortality. Initial studies have shown that renal denervation is able to reduce not only blood pressure but also heart rate, and is associated with a reduction in myocardial hypertrophy, improved glucose tolerance, and ameliorated microalbuminuria. Since some experimental and observational data suggest an antiarrhythmic effect, it is possible that renal denervation might also play a therapeutic role in arrhythmias often occurring in chronic heart failure. The first proof-of-concept studies are planned to evaluate the clinical effect of this pathophysiologically plausible method, which might be able to change clinical practice.
Topics: Blood Pressure; Heart Failure; Heart Rate; Humans; Kidney; Sympathectomy; Sympathetic Nervous System; Treatment Outcome
PubMed: 24644008
DOI: 10.1002/ejhf.83 -
Hypertension Research : Official... Feb 2022
Topics: Denervation; Kidney
PubMed: 34912048
DOI: 10.1038/s41440-021-00808-w -
Cleveland Clinic Journal of Medicine Sep 2017Despite promising results in initial trials, renal denervation failed to achieve its efficacy end points as a treatment for resistant hypertension in the SYMPLICITY... (Review)
Review
Despite promising results in initial trials, renal denervation failed to achieve its efficacy end points as a treatment for resistant hypertension in the SYMPLICITY HTN-3 trial, the largest trial of this treatment to date (N Engl J Med 2014; 370:1393-1401). Is renal denervation dead, or will future trials and newer technology revive it?
Topics: Blood Pressure; Denervation; Humans; Hypertension; Kidney; Sympathectomy
PubMed: 28885911
DOI: 10.3949/ccjm.84a.14129 -
American Journal of Hypertension Jun 2011Essential hypertension remains one of the biggest challenges in medicine with an enormous impact on both individual and society levels. With the exception of relatively... (Review)
Review
Essential hypertension remains one of the biggest challenges in medicine with an enormous impact on both individual and society levels. With the exception of relatively rare monogenetic forms of hypertension, there is now general agreement that the condition is multifactorial in nature and hence requires therapeutic approaches targeting several aspects of the underlying pathophysiology. Accordingly, all major guidelines promote a combination of lifestyle interventions and combination pharmacotherapy to reach target blood pressure (BP) levels in order to reduce overall cardiovascular risk in affected patients. Although this approach works for many, it fails in a considerable number of patients for various reasons including drug-intolerance, noncompliance, physician inertia, and others, leaving them at unacceptably high cardiovascular risk. The quest for additional therapeutic approaches to safely and effectively manage hypertension continues and expands to the reappraisal of older concepts such as renal denervation. Based on the robust preclinical and clinical data surrounding the role of renal sympathetic nerves in various aspects of BP control very recent efforts have led to the development of a novel catheter-based approach using radiofrequency (RF) energy to selectively target and disrupt the renal nerves. The available evidence from the limited number of uncontrolled hypertensive patients in whom renal denervation has been performed are auspicious and indicate that the procedure has a favorable safety profile and is associated with a substantial and presumably sustained BP reduction. Although promising, a myriad of questions are far from being conclusively answered and require our concerted research efforts to explore the full potential and possible risks of this approach. Here we briefly review the science surrounding renal denervation, summarize the current data on safety and efficacy of renal nerve ablation, and discuss some of the open questions that need to be addressed in the near future.
Topics: Aged; Animals; Blood Pressure; Cardiovascular Diseases; Catheter Ablation; Denervation; Humans; Hypertension; Kidney; Middle Aged; Risk; Sympathectomy; Sympathetic Nervous System
PubMed: 21394087
DOI: 10.1038/ajh.2011.35 -
Hellenic Journal of Cardiology : HJC =... 2020Currently, renal denervation (RDN) has proven its overall procedural and renal safety in registries and trials. Available data, suggest that vascular complications are...
Currently, renal denervation (RDN) has proven its overall procedural and renal safety in registries and trials. Available data, suggest that vascular complications are rather scarce in modern studies using established neuromodulation catheters of different technologies and kidney parameters are mainly maintained stable overtime in RDN patients. Identification of the impact of energy delivery at vascular level by means of advanced methodologies such as optical coherence tomography (OCT) is a meaningful research tool. This accumulation of evidence on the acute and late effects of the procedure in the renal artery tissue especially when a new catheter is tested, as in the present work can further enhance our knowledge on the pathophysiology and clinical outcome of RDN.
Topics: Blood Pressure; Catheter Ablation; Denervation; Humans; Hypertension; Kidney; Renal Artery; Sympathectomy; Treatment Outcome
PubMed: 32916295
DOI: 10.1016/j.hjc.2020.09.002