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Background: Electro-anatomic 3D mapping systems enable the fluoroscopy (FL) exposure to be reduced. In right-heart supraventricular tachycardia (SVT) procedures, FL could potentially be avoided. Our aim was to discuss some steps focusing on safety. Methods and results: The patient cohort comprised 70 consecutive SVT patients who underwent electrophysiologic (EP) catheterization. FL was routinely avoided in all cases (54.2% males, age 57.2 ± 13.3 years): 51 ablations and 19 EP study procedures. The Carto®3 (Biosense Webster) mapping system was used in 17/70 cases (24.3%), and the EnSite Precision™ (Abbott) system in the remaining 53/70 (75.7%). The mean procedure time was 94.1 ± 33.2 min; no FL was used. No major complications occurred. Acute procedural success was achieved in all 51 patients who underwent ablation. Over 3-month follow-up, arrhythmia recurred in 1 patient. There were no significant differences in procedural times between the two mapping systems, except for the time dedicated to the full geometry creation, which was longer for the EnSite Precision™ system: 10 min (8.5–15 IQR) vs 8 min (5–10 IQR) for the Carto® system (p

Purpose Recent studies and our preliminary data demonstrate that muscle-specific ablation of the autophagy-related protein Atg7, leads to block of autophagy, sarcopenia and destabilization of the neuro-muscular junction (NMJ). In addition, Atg7 knock-out (Atg7 KO) muscle fibers release exosomes containing the muscle specific, miR-206, which is consistently elevated in the plasma. Interestingly, we found that miR-206 content was elevated in the heart, suggesting cardiac uptake of the miR-carrying circulating exosomes. We thus aimed at defining the effects of miR-206 on heart homeostasis. Methods Here, we analyzed the cardiac phenotype of adult (12mo.) and aged (24mo.) Atg7 KO mice, as well as of adult C57BL/6J mice injected, via tail vein, with scramble- or miR-206-loaded exosomes. Exosomes were isolated from EDL muscle of control and Atg7 KO mice, as well as from HEK293 cells. Heart function was assessed by echocardiography and ECG-telemetry. Confocal IF, whole-mount IF on heart blocks and multiphoton imaging were used to assess heart structure and sympathetic innervation. Bioinformatics, molecular and biochemical analyses were performed to identify novel targets of miR-206. IF, BRET assay and imaging of TrKA translocation were performed in cultured sympathetic neurons (SNs). Results We demonstrate that circulating exosomes, containing miR-206, are taken up by the heart leading to sympathetic dysinnervation, accompanied to reduction in the neurogenic control of cardiac rhythm and increased arrhythmogenesis. In vitro assays demonstrated that exosome-carried miR-206 targets cardiac SNs (cSNs), compromising cell structure and function. Indeed, increased miR-206 expression is accompanied by cSN atrophy, irregular axonal distribution of the active neurotransmitter release sites, and reduction in axonal sprouting. These effects are likely attributed to the miR-206-mediated down-regulation of the NGF receptor p75, as demonstrated by bioinformatics, luciferase assay, molecular and biochemical analyses in vitro and ex vivo. BRET assay, performed in cultured SNs treated with exosomes carrying miR-206, showed reduced formation of p75/TrkA complexes, which generate high-affinity binding sites for NGF and enhance neurotrophin responsiveness. Consistent with impaired NGF retrograde transport, miR-206 over-expressing SNs displayed reduced NGF protein content and decreased phosphorylation of Akt, which is an NGF downstream target, regulating neuronal survival. Interestingly, these latter results were confirmed in the stellate ganglia from Atg KO and miR-206 treated mice. miR-206 causes heart dysinnervation Conclusions We identify miR-206 as a key molecular player in the “muscle-to-heart” communication. miR-206 may participate to the pathogenesis of secondary cardiac dysfunction in skeletal muscle diseases associated to increased circulating levels of miR-206, ranging from ageing to neurodegenerative disorders (i.e. ALS, DMD).

Mitochondrial quality control is essential in highly structured cells such as neurons and muscles. In skeletal muscle the mitochondrial fission proteins are reduced in different physiopathological conditions including ageing sarcopenia, cancer cachexia and chemotherapy-induced muscle wasting. However, whether mitochondrial fission is essential for muscle homeostasis is still unclear. Here we show that muscle-specific loss of the pro-fission dynamin related protein (DRP) 1 induces muscle wasting and weakness. Constitutive Drp1 ablation in muscles reduces growth and causes animal death while inducible deletion results in atrophy and degeneration. Drp1 deficient mitochondria are morphologically bigger and functionally abnormal. The dysfunctional mitochondria signals to the nucleus to induce the ubiquitin-proteasome system and an Unfolded Protein Response while the change of mitochondrial volume results in an increase of mitochondrial Ca2+ uptake and myofiber death. Our findings reveal that morphology of mitochondrial network is critical for several biological processes that control nuclear programs and Ca2+ handling., Muscle loss is associated with altered expression of proteins involved in mitochondrial homeostasis, but whether this is causative remains unclear. Here, the authors show that genetic ablation of the pro-fission protein DRP1 leads to accumulation of abnormal mitochondria that induce muscle atrophy by altering Ca2+ homeostasis and cellular stress responses.

Summary Mitochondrial dysfunction occurs during aging, but its impact on tissue senescence is unknown. Here, we find that sedentary but not active humans display an age-related decline in the mitochondrial protein, optic atrophy 1 (OPA1), that is associated with muscle loss. In adult mice, acute, muscle-specific deletion of Opa1 induces a precocious senescence phenotype and premature death. Conditional and inducible Opa1 deletion alters mitochondrial morphology and function but not DNA content. Mechanistically, the ablation of Opa1 leads to ER stress, which signals via the unfolded protein response (UPR) and FoxOs, inducing a catabolic program of muscle loss and systemic aging. Pharmacological inhibition of ER stress or muscle-specific deletion of FGF21 compensates for the loss of Opa1, restoring a normal metabolic state and preventing muscle atrophy and premature death. Thus, mitochondrial dysfunction in the muscle can trigger a cascade of signaling initiated at the ER that systemically affects general metabolism and aging., Graphical Abstract, Highlights • OPA1 is a physical activity sensor that is downregulated during aging sarcopenia • Muscle OPA1 controls general metabolism and epithelial senescence via FGF21 • Inhibition of muscle OPA1 induces a systemic pro-inflammatory status • OPA1 controls protein breakdown/synthesis, muscle stem cells and fiber innervation, Aging has been reported to be accompanied by changes in mitochondrial dynamics, but the impact on tissue senescence is unknown. Tezze et al. show that deletion of Opa1 impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence and identify FGF21 as the culprit of precocious aging and premature death.