Muscle denervation promotes functional interactions between glial and mesenchymal cells through NGFR and NGF.

We performed scRNA-seq/snATAC-seq of skeletal muscles post sciatic nerve transection to delineate cell type-specific patterns of gene expression/chromatin accessibility at different time points post-denervation. Unlike myotrauma, denervation selectively activates glial cells and Thy1/CD90-expressing mesenchymal cells. Glial cells expressed Ngf receptor (Ngfr) and were located near neuromuscular junctions (NMJs), close to Thy1/CD90-expressing cells, which provided the main cellular source of NGF post-denervation. Functional communication between these cells was mediated by NGF/NGFR, as either recombinant NGF or co-culture with Thy1/CD90-expressing cells could increase glial cell number ex vivo. Pseudo-time analysis in glial cells revealed an initial bifurcation into processes related to either cellular de-differentiation/commitment to specialized cell types (e.g., Schwann cells), or failure to promote nerve regeneration, leading to extracellular matrix remodeling toward fibrosis. Thus, interactions between denervation-activated Thy1/CD90-expressing and glial cells represent an early abortive process toward NMJs repair, ensued by the conversion of denervated muscles into an environment hostile for NMJ repair.

Spatially resolved transcriptomics reveals innervation-responsive functional clusters in skeletal muscle.

Striated muscle is a highly organized structure composed of well-defined anatomical domains with integrated but distinct assignments. So far, the lack of a direct correlation between tissue architecture and gene expression has limited our understanding of how each unit responds to physio-pathologic contexts. Here, we show how the combined use of spatially resolved transcriptomics and immunofluorescence can bridge this gap by enabling the unbiased identification of such domains and the characterization of their response to external perturbations. Using a spatiotemporal analysis, we follow changes in the transcriptome of specific domains in muscle in a model of denervation. Furthermore, our approach enables us to identify the spatial distribution and nerve dependence of atrophic signaling pathway and polyamine metabolism to glycolytic fibers. Indeed, we demonstrate that perturbations of polyamine pathway can affect muscle function. Our dataset serves as a resource for future studies of the mechanisms underlying skeletal muscle homeostasis and innervation.

Metabolic Remodeling in Skeletal Muscle Atrophy as a Therapeutic Target.

Skeletal muscle is a highly responsive tissue, able to remodel its size and metabolism in response to external demand. Muscle fibers can vary from fast glycolytic to slow oxidative, and their frequency in a specific muscle is tightly regulated by fiber maturation, innervation, or external causes. Atrophic conditions, including aging, amyotrophic lateral sclerosis, and cancer-induced cachexia, differ in the causative factors and molecular signaling leading to muscle wasting; nevertheless, all of these conditions are characterized by metabolic remodeling, which contributes to the pathological progression of muscle atrophy. Here, we discuss how changes in muscle metabolism can be used as a therapeutic target and review the evidence in support of nutritional interventions and/or physical exercise as tools for counteracting muscle wasting in atrophic conditions.

Activation of skeletal muscle-resident glial cells upon nerve injury.

Here, we report on the identification of Itga7-expressing muscle-resident glial cells activated by loss of neuromuscular junction (NMJ) integrity. Gene expression analysis at the bulk and single-cell level revealed that these cells are distinct from Itga7-expressing muscle satellite cells. We show that a selective activation and expansion of Itga7+ glial cells occur in response to muscle nerve lesion. Upon activation, muscle glial-derived progenies expressed neurotrophic genes, including nerve growth factor receptor, which enables their isolation by FACS. We show that activated muscle glial cells also expressed genes potentially implicated in extracellular matrix remodeling at NMJs. We found that tenascin C, which was highly expressed by muscle glial cells, activated upon nerve injury and preferentially localized to NMJ. Interestingly, we observed that the activation of muscle glial cells by acute nerve injury was reversible upon NMJ repair. By contrast, in a mouse model of ALS, in which NMJ degeneration is progressive, muscle glial cells steadily increased over the course of the disease. However, they exhibited an impaired neurotrophic activity, suggesting that pathogenic activation of glial cells may be implicated in ALS progression.

Evaluation of plantar fasciopathy shear wave elastography: a comparison between patients and healthy subjects.

PURPOSE: The aim of this study is to compare elasticity features between patients with plantar fasciitis (PFis) and an asymptomatic healthy control group using shear wave elastography (SWE) and to correlate SWE values with clinical scores. METHODS: Consecutive patients diagnosed with PFis and asymptomatic subjects were enrolled in the present study. Both groups underwent clinical, ultrasound (US), and SWE evaluation. A plantar fascia thickness > 4 mm was considered pathognomonic of PFis. SWE stiffness elasticity (Young's modulus in kPa and shear wave velocity in m/s) was measured 1 cm distally from the calcaneal insertion. Correlations with VAS and the 17-Italian Foot Function Index (17-FFI) were determined. RESULTS: A total of 19 patients satisfied the inclusion criteria for the patient group and were enrolled in the study, and 21 healthy subjects were used as a control group. Statistically significant differences were found for shear wave velocity between the patient and the control group, with SWE findings of 3.8 (5.1; 1.5) m/s and 4.7 (4.07; 7.04) m/s, respectively (p = 0.006). Strong positive correlations were found between the SWE findings and both the pain and the functional scale (VAS: p = 0.001; FFI: p = 0.012). CONCLUSION: SWE allows quantitative assessment of the stiffness of the plantar fascia and can show PFis alterations, increasing the diagnostic performance of B-mode US. In addition, SWE shows a strong correlation with clinical scores, improving patient assessment and follow-up.

Elastosonographic evaluation after extracorporeal shockwave treatment in plantar fasciopathy.

AIM: To assess the ultrasound features in patients with plantar fasciopathy before and after extracorporeal shock waves therapy (ESWT), using conventional grey-scale imaging and both strain (SE) and shear wave (SWE) elastosonographic evaluation. MATERIAL AND METHOD: Consecutive patients of both sexes attending our outpatient's clinic, with diagnosis of unilateral plantar fasciopathy, were enrolled. Patients were treated with 3 sessions of ESWT once a week, and underwent clinical and ultrasound evaluation at baseline and at one and three months after treatment. Roles and Maudsley score (RM), visual analog scale (VAS) and 17-Italian Foot Function Index (FFI), were used to assess pain and functional improvement. RESULTS: Twenty patients (11 female and 9 male) were enrolled in the study. Contralateral asymptomatic healthy plantar fascia was used as a control. At baseline, SWE velocity (SWEv) showed statistically significant difference between affected 3.8 (1.5; 5.1) m/s and healthy side 4.7 (4.07; 7.04) m/s, (p=0.006); no significant difference was found for strain ratio values (p=0.656). SWEv post hoc test results showed a significant difference from baseline 3.8 (1.5-5.1) m/s and three month 5.23 (4.55-6.74) m/s follow up visit (p=0.003). Significant statistical negative correlation was found between the SWEv and VAS (p=0.001) and positive correlation between the SWEv and FFI (p=0.012). CONCLUSION: SWE was effective in assessing plantar fascia elasticity and its alteration in fasciopathy. Furthermore, on the basis of the correlation with pain and functional scales, this technique appears to be a useful additional technique to conventional ultrasound for monitoring the efficacy of treatment.

Helicobacter pylori infection in obesity and its clinical outcome after bariatric surgery.

The present review summarizes the prevalence and active clinical problems in obese patients with Helicobacter pylori (H. pylori) infection, as well as the outcomes after bariatric surgery in this patient population. The involvement of H. pylori in the pathophysiology of obesity is still debated. It may be that the infection is protective against obesity, because of the gastritis-induced decrease in production and secretion of the orexigenic hormone ghrelin. However, recent epidemiological studies have failed to show an association between H. pylori infection and reduced body mass index. H. pylori infection might represent a limiting factor in the access to bariatric bypass surgery, even if high-quality evidence indicating the advantages of preoperative H. pylori screening and eradication is lacking. The clinical management of infection is complicated by the lower eradication rates with standard therapeutic regimens reported in obese patients than in the normal-weight population. Prospective clinical studies to ameliorate both H. pylori eradication rates and control the clinical outcomes of H. pylori infection after different bariatric procedures are warranted.