Thbs1 regulates skeletal muscle mass in a TGFβ-Smad2/3-ATF4-dependent manner.

Loss of muscle mass is a feature of chronic illness and aging. Here, we report that skeletal muscle-specific thrombospondin-1 transgenic mice (Thbs1 Tg) have profound muscle atrophy with age-dependent decreases in exercise capacity and premature lethality. Mechanistically, Thbs1 activates transforming growth factor β (TGFβ)-Smad2/3 signaling, which also induces activating transcription factor 4 (ATF4) expression that together modulates the autophagy-lysosomal pathway (ALP) and ubiquitin-proteasome system (UPS) to facilitate muscle atrophy.

MCU-independent Ca uptake mediates mitochondrial Ca overload and necrotic cell death in a mouse model of Duchenne muscular dystrophy.

Mitochondrial Ca overload can mediate mitochondria-dependent cell death, a major contributor to several human diseases. Indeed, Duchenne muscular dystrophy (MD) is driven by dysfunctional Ca influx across the sarcolemma that causes mitochondrial Ca overload, organelle rupture, and muscle necrosis. The mitochondrial Ca uniporter (MCU) complex is the primary characterized mechanism for acute mitochondrial Ca uptake.

MCUb is an inducible regulator of calcium-dependent mitochondrial metabolism and substrate utilization in muscle.

Mitochondria use the electron transport chain to generate high-energy phosphate from oxidative phosphorylation, a process also regulated by the mitochondrial Ca uniporter (MCU) and Ca levels. Here, we show that MCUb, an inhibitor of MCU-mediated Ca influx, is induced by caloric restriction, where it increases mitochondrial fatty acid utilization. To mimic the fasted state with reduced mitochondrial Ca influx, we generated genetically altered mice with skeletal muscle-specific MCUb expression that showed greater fatty acid usage, less fat accumulation, and lower body weight.

ANT-dependent MPTP underlies necrotic myofiber death in muscular dystrophy.

Mitochondrial permeability transition pore (MPTP) formation contributes to ischemia-reperfusion injury in the heart and several degenerative diseases, including muscular dystrophy (MD). MD is a family of genetic disorders characterized by progressive muscle necrosis and premature death. It has been proposed that the MPTP has two molecular components, the adenine nucleotide translocase (ANT) family of proteins and an unknown component that requires the chaperone cyclophilin D (CypD) to activate.

A 20/20 view of ANT function in mitochondrial biology and necrotic cell death.

The adenosine nucleotide translocase (ANT) family of proteins are inner mitochondrial membrane proteins involved in energy homeostasis and cell death. The primary function of ANT proteins is to exchange cytosolic ADP with matrix ATP, facilitating the export of newly synthesized ATP to the cell while providing new ADP substrate to the mitochondria. As such, the ANT proteins are central to maintaining energy homeostasis in all eukaryotic cells.

MCUb Induction Protects the Heart From Postischemic Remodeling.

Rationale: Mitochondrial Ca loading augments oxidative metabolism to match functional demands during times of increased work or injury. However, mitochondrial Ca overload also directly causes mitochondrial rupture and cardiomyocyte death during ischemia-reperfusion injury by inducing mitochondrial permeability transition pore opening. The MCU (mitochondrial Ca uniporter) mediates mitochondrial Ca influx, and its activity is modulated by partner proteins in its molecular complex, including the MCUb subunit.

A novel class of cardioprotective small-molecule PTP inhibitors.

Ischemia/reperfusion (I/R) injury is mediated in large part by opening of the mitochondrial permeability transition pore (PTP). Consequently, inhibitors of the PTP hold great promise for the treatment of a variety of cardiovascular disorders. At present, PTP inhibition is obtained only through the use of drugs (e.

Inhibition of mitochondrial permeability transition by deletion of the ANT family and CypD.

The mitochondrial permeability transition pore (MPTP) has resisted molecular identification. The original model of the MPTP that proposed the adenine nucleotide translocator (ANT) as the inner membrane pore-forming component was challenged when mitochondria from Ant1/2 double null mouse liver still had MPTP activity. Because mice express three genes, we reinvestigated whether the ANTs comprise the MPTP.

The mitochondrial calcium uniporter underlies metabolic fuel preference in skeletal muscle.

The mitochondrial Ca2+ uniporter (MCU) complex mediates acute mitochondrial Ca2+ influx. In skeletal muscle, MCU links Ca2+ signaling to energy production by directly enhancing the activity of key metabolic enzymes in the mitochondria. Here, we examined the role of MCU in skeletal muscle development and metabolic function by generating mouse models for the targeted deletion of Mcu in embryonic, postnatal, and adult skeletal muscle.

Cardiac Ryanodine Receptor (Ryr2)-mediated Calcium Signals Specifically Promote Glucose Oxidation via Pyruvate Dehydrogenase.

Cardiac ryanodine receptor (Ryr2) Ca release channels and cellular metabolism are both disrupted in heart disease. Recently, we demonstrated that total loss of Ryr2 leads to cardiomyocyte contractile dysfunction, arrhythmia, and reduced heart rate. Acute total Ryr2 ablation also impaired metabolism, but it was not clear whether this was a cause or consequence of heart failure.

Reduced Insulin Production Relieves Endoplasmic Reticulum Stress and Induces β Cell Proliferation.

Pancreatic β cells are mostly post-mitotic, but it is unclear what locks them in this state. Perturbations including uncontrolled hyperglycemia can drive β cells into more pliable states with reduced cellular insulin levels, increased β cell proliferation, and hormone mis-expression, but it is unknown whether reduced insulin production itself plays a role. Here, we define the effects of ∼50% reduced insulin production in Ins1(-/-):Ins2(f/f):Pdx1Cre(ERT):mTmG mice prior to robust hyperglycemia.

Generation and characterization of a mouse model harboring the exon-3 deletion in the cardiac ryanodine receptor.

A large genomic deletion in human cardiac ryanodine receptor (RYR2) gene has been detected in a number of unrelated families with various clinical phenotypes, including catecholaminergic polymorphic ventricular tachycardia (CPVT). This genomic deletion results in an in-frame deletion of exon-3 (Ex3-del). To understand the underlying disease mechanism of the RyR2 Ex3-del mutation, we generated a mouse model in which the RyR2 exon-3 sequence plus 15-bp intron sequences flanking exon-3 were deleted.

Hyperglycemia-induced secretion of endothelial heparanase stimulates a vascular endothelial growth factor autocrine network in cardiomyocytes that promotes recruitment of lipoprotein lipase.

Objective: During diabetes mellitus, coronary lipoprotein lipase increases to promote the predominant use of fatty acids. We have reported that high glucose stimulates active heparanase secretion from endothelial cells to cleave cardiomyocyte heparan sulfate and release bound lipoprotein lipase for transfer to the vascular lumen. In the current study, we examined whether heparanase also has a function to release cardiomyocyte vascular endothelial growth factor (VEGF), and whether this growth factor influences cardiomyocyte fatty acid delivery in an autocrine manner.

Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo.

Ca(2+) fluxes between adjacent organelles are thought to control many cellular processes, including metabolism and cell survival. In vitro evidence has been presented that constitutive Ca(2+) flux from intracellular stores into mitochondria is required for basal cellular metabolism, but these observations have not been made in vivo. We report that controlled in vivo depletion of cardiac RYR2, using a conditional gene knock-out strategy (cRyr2KO mice), is sufficient to reduce mitochondrial Ca(2+) and oxidative metabolism, and to establish a pseudohypoxic state with increased autophagy.

Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice.

Aims: The molecular mechanisms controlling heart function and rhythmicity are incompletely understood. While it is widely accepted that the type 2 ryanodine receptor (Ryr2) is the major Ca(2+) release channel in excitation-contraction coupling, the role of these channels in setting a consistent beating rate remains controversial. Gain-of-function RYR2 mutations in humans and genetically engineered mouse models are known to cause Ca(2+) leak, arrhythmias, and sudden cardiac death.

Nanospaces between endoplasmic reticulum and mitochondria as control centres of pancreatic β-cell metabolism and survival.

Nanometre-scale spaces between organelles represent focused nodes for signal transduction and the control of cellular decisions. The endoplasmic reticulum (ER) and the mitochondria form dynamic quasi-synaptic interaction nanodomains in all cell types examined, but the functional role of these junctions in cellular metabolism and cell survival remains to be fully understood. In this paper, we review recent evidence that ER Ca(2+) channels, such as the RyR and IP(3)R, can signal specifically across this nanodomain to the adjacent mitochondria to pace basal metabolism, with focus on the pancreatic β-cell.