DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass.

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.

Safety steps for a non-fluoroscopic approach in right-sided electrophysiology procedures: A point of view.

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 ±â€¯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 ±â€¯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 < 0.001) mainly due to the sub-diaphragmatic navigation. The following procedural steps were considered critical in order to safely avoid FL use: "loop" advancing of catheters, the use of a fixed intracardiac reference, His signal landmark centered maps and the careful acquisition of sub-diaphragmatic extracardiac geometry. CONCLUSIONS: A routine zero X-ray approach by means of electro-anatomic 3D mapping systems is safe and effective in right-atrium procedures. Some ad-hoc discussed procedural steps may enhance safety.

Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence.

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.