PHAF1/MYTHO is a novel autophagy regulator that controls muscle integrity.

Skeletal muscles play key roles in movement, posture, thermogenesis, and whole-body metabolism. Autophagy plays essential roles in the regulation of muscle mass, function and integrity. However, the molecular machinery that regulates autophagy is still incompletely understood.

Parkin: a potential target to promote healthy ageing.

Parkin is an E3 ubiquitin ligase mostly known for its role in regulating the removal of defective mitochondria via mitophagy. However, increasing experimental evidence that Parkin regulates several other aspects of mitochondrial biology in addition to its role in mitophagy has emerged over the past two decades. Indeed, Parkin has been shown to regulate mitochondrial biogenesis and dynamics and mitochondria-derived vesicle formation, suggesting that Parkin plays key roles in maintaining healthy mitochondria.

Role of Human Antigen R (HuR) in the Regulation of Pulmonary ACE2 Expression.

Patients with COPD may be at an increased risk for severe illness from COVID-19 because of ACE2 upregulation, the entry receptor for SARS-CoV-2. Chronic exposure to cigarette smoke, the main risk factor for COPD, increases pulmonary ACE2. How ACE2 expression is controlled is not known but may involve HuR, an RNA binding protein that increases protein expression by stabilizing mRNA.

Regulation of muscle and mitochondrial health by the mitochondrial fission protein Drp1 in aged mice.

Key Points: The maintenance of mitochondrial integrity is critical for skeletal muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in the muscle ageing process remains unclear. Here we report that both Drp1 knockdown and Drp1 overexpression late in life in mice is detrimental to skeletal muscle function and mitochondrial health.

Roles of miR-640 and Zinc Finger Protein 91 (ZFP91) in Angiopoietin-1-Induced In Vitro Angiogenesis.

Angiopoietin-1 (Ang-1) is a ligand of Tie-2 receptors that promotes angiogenesis. It has been established that regulatory loops exist between angiogenic growth factors and distinct pro or anti-angiogenic miRNAs, but the nature and the roles of Ang-1-regulated miRNAs remain unclear. In this study, we assessed the role of miR-640 in Ang-1-induced angiogenesis in human umbilical vein endothelial cells (HUVECs).

Drp1 knockdown induces severe muscle atrophy and remodelling, mitochondrial dysfunction, autophagy impairment and denervation.

Key Points: The maintenance of optimal mitochondrial content and function is critical for muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control; however, the exact role that mitochondrial fission plays in skeletal muscle health remains unclear. Here we report knocking down Drp1 (a protein regulating mitochondrial fission) for 4 months in adult mouse skeletal muscle resulted in severe muscle atrophy (40-50%).

Oxidants Regulated Diaphragm Proteolysis during Mechanical Ventilation in Rats.

What We Already Know About This Topic: Diaphragm dysfunction and atrophy develop during controlled mechanical ventilation. Although oxidative stress injures muscle during controlled mechanical ventilation, it is unclear whether it causes autophagy or fiber atrophy.

What This Article Tells Us That Is New: Pretreatment of rats undergoing 24 h of mechanical ventilation with N-acetylcysteine prevents decreases in diaphragm contractility, inhibits the autophagy and proteasome pathways, but has no influence on the development of diaphragm fiber atrophy.

Parkin overexpression protects from ageing-related loss of muscle mass and strength.

Key Points: Recent evidence suggests that impaired mitophagy, a process in charge of removing damaged/dysfunctional mitochondria and in part regulated by Parkin, could contribute to the ageing-related loss of muscle mass and function. In the present study, we show that Parkin overexpression attenuates ageing-related loss of muscle mass and strength and unexpectedly causes hypertrophy in adult skeletal muscles. We also show that Parkin overexpression leads to increases in mitochondrial content and enzymatic activities.

Ventilator-induced diaphragmatic dysfunction in MDX mice.

Introduction: Patients with Duchenne muscular dystrophy (DMD) frequently undergo mechanical ventilation (MV) for treatment of hypoventilation, but the susceptibility of the dystrophic diaphragm to ventilator-induced diaphragmatic dysfunction (VIDD) has not been examined.

Methods: Dystrophic mice (mdx-genetic homolog of DMD) were assigned to non-ventilated control (CTL) and MV (for 6 hours) groups. Biochemical markers of oxidative/cellular stress, metabolism, and proteolysis were compared along with ex-vivo diaphragmatic force production.

Failed reinnervation in aging skeletal muscle.

Background: Skeletal muscle displays a marked accumulation of denervated myofibers at advanced age, which coincides with an acceleration of muscle atrophy.

Methods: In this study, we evaluated the hypothesis that the accumulation of denervated myofibers in advanced age is due to failed reinnervation by examining muscle from young adult (YA) and very old (VO) rats and from a murine model of sporadic denervation secondary to neurotrypsin over-expression (Sarco mouse).

Results: Both aging rat muscle and Sarco mouse muscle exhibited marked fiber-type grouping, consistent with repeating cycles of denervation and reinnervation, yet in VO muscle, rapsyn at the endplate increased and was associated with only a 10 % decline in acetylcholine receptor (AChR) intensity, whereas in Sarco mice, there was a decline in rapsyn and a 25 % decrease in AChR intensity.

Fibulin-5 Regulates Angiopoietin-1/Tie-2 Receptor Signaling in Endothelial Cells.

Background: Fibulin-5 is an extracellular matrix glycoprotein that plays critical roles in vasculogenesis and embryonic development. Deletion of Fibulin-5 in mice results in enhanced skin vascularization and upregulation of the angiogenesis factor angiopoietin-1 (Ang-1), suggesting that Fibulin-5 functions as an angiogenesis inhibitor. In this study, we investigate the inhibitory effects of Fibulin-5 on Ang-1/TIE-2 receptor pathway signaling and cell survival in human endothelial cells.

Mechanisms of Chronic Muscle Wasting and Dysfunction after an Intensive Care Unit Stay. A Pilot Study.

Rationale: Critical illness survivors often experience permanent functional disability due to intensive care unit (ICU)-acquired weakness. The mechanisms responsible for long-term weakness persistence versus resolution are unknown.

Objectives: To delineate cellular mechanisms underlying long-term weakness persistence in ICU survivors.

Prolonged controlled mechanical ventilation in humans triggers myofibrillar contractile dysfunction and myofilament protein loss in the diaphragm.

Background: Prolonged controlled mechanical ventilation (CMV) in humans and experimental animals results in diaphragm fibre atrophy and injury. In animals, prolonged CMV also triggers significant declines in diaphragm myofibril contractility. In humans, the impact of prolonged CMV on myofibril contractility remains unknown.

Contribution of the Mitochondria to Locomotor Muscle Dysfunction in Patients With COPD.

COPD is a significant public health challenge, notably set to become the third leading cause of death and fifth leading cause of chronic disability worldwide by the next decade. Skeletal muscle impairment is now recognized as a disabling, extrapulmonary consequence of COPD that is associated with reduced quality of life and premature mortality. Because COPD typically manifests in older individuals, these clinical features may overlie normal age-associated declines in muscle function and performance.

Ventilator-induced diaphragmatic dysfunction: what have we learned?

Purpose Of Review: The purpose of the review is to summarize and discuss recent research regarding the role of mechanical ventilation in producing weakness and atrophy of the diaphragm in critically ill patients, an entity termed ventilator-induced diaphragmatic dysfunction (VIDD).

Recent Findings: Severe weakness of the diaphragm is frequent in mechanically ventilated patients, in whom it contributes to poor outcomes including increased mortality. Significant progress has been made in identifying the molecular mechanisms responsible for VIDD in animal models, and there is accumulating evidence for occurrence of the same cellular processes in the diaphragms of human patients undergoing prolonged mechanical ventilation.

Muscle cell derived angiopoietin-1 contributes to both myogenesis and angiogenesis in the ischemic environment.

Recent strategies to treat peripheral arterial disease (PAD) have focused on stem cell based therapies, which are believed to result in local secretion of vascular growth factors. Little is known, however, about the role of ischemic endogenous cells in this context. We hypothesized that ischemic muscle cells (MC) are capable of secreting growth factors that act as potent effectors of the local cellular regenerative environment.

Angiopoietin-1 inhibits toll-like receptor 4 signalling in cultured endothelial cells: role of miR-146b-5p.

Aims: Bacterial lipopolysaccharides (LPS) induce innate immune inflammatory responses in endothelial cells by activating toll-like receptor 4 (TLR4) signalling. Here, we investigate the effects of angiopoietin-1 (Ang-1) on LPS-induced TLR4 signalling and the role of the miR-146 family of micro RNAs in the effects of Ang-1 on TRL4 signalling.

Methods And Results: Leucocyte adhesion to human umbilical vein endothelial cells (HUVECs) was detected using fluorescence microscopy.

Angiopoietin-1 enhances skeletal muscle regeneration in mice.

Activation of muscle progenitor cell myogenesis and endothelial cell angiogenesis is critical for the recovery of skeletal muscle from injury. Angiopoietin-1 (Ang-1), a ligand of Tie-2 receptors, enhances angiogenesis and skeletal muscle satellite cell survival; however, its role in skeletal muscle regeneration after injury is unknown. We assessed the effects of Ang-1 on fiber regeneration, myogenesis, and angiogenesis in injured skeletal muscle (tibialis anterior, TA) in mice.

Effects of controlled mechanical ventilation on sepsis-induced diaphragm dysfunction in rats.

Objectives: Diaphragm dysfunction develops during severe sepsis as a consequence of hemodynamic, metabolic, and intrinsic abnormalities. Similarly, 12 hours of controlled mechanical ventilation also promotes diaphragm dysfunction. Importantly, patients with sepsis are often treated with mechanical ventilation for several days.

The JAK-STAT pathway is critical in ventilator-induced diaphragm dysfunction.

Mechanical ventilation (MV) is one of the lynchpins of modern intensive-care medicine and is life saving in many critically ill patients. Continuous ventilator support, however, results in ventilation-induced diaphragm dysfunction (VIDD) that likely prolongs patients' need for MV and thereby leads to major associated complications and avoidable intensive care unit (ICU) deaths. Oxidative stress is a key pathogenic event in the development of VIDD, but its regulation remains largely undefined.

An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease.

Background: Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications.

Purpose: The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD.