Summary Activating mutations in BRAF are the most common genetic alterations in melanoma. Inhibition of BRAF by small molecule inhibitors leads to cell cycle arrest and apoptosis. We show here that BRAF inhibition also induces an oxidative phosphorylation gene program, mitochondrial biogenesis, and the increased expression of the mitochondrial master regulator, PGC1α. We further show that a target of BRAF, the melanocyte lineage factor MITF, directly regulates the expression of PGC1α. Melanomas with activation of the BRAF/MAPK pathway have suppressed levels of MITF and PGC1α, and decreased oxidative metabolism. Conversely, treatment of BRAF mutated melanomas with BRAF inhibitors renders them addicted to oxidative phosphorylation. Our data thus identify an adaptive metabolic program that limits the efficacy of BRAF inhibitors.

Abstract-Peripartum cardiomyopathy is a potentially life-threatening pregnancy-associated disease that typically arises in the peripartum period and is marked by left ventricular dysfunction and heart failure. The disease is relatively uncommon, but its incidence is rising. Women often recover cardiac function, but long-lasting morbidity and mortality are not infrequent. Management of peripartum cardiomyopathy is largely limited to the same neurohormonal antagonists used in other forms of cardiomyopathy, and no proven disease-specific therapies exist yet. Research in the past decade has suggested that peripartum cardiomyopathy is caused by vascular dysfunction, triggered by late-gestational maternal hormones. Most recently, information has also indicated that many cases of peripartum cardiomyopathy have genetic underpinnings. We review here the known epidemiology, clinical presentation, and management of peripartum cardiomyopathy, as well as the current knowledge of the pathophysiology of the disease.

SUMMARY A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD+ precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1-7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD+ precursor nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.

Abstract:The beating heart requires a constant flux of ATP to maintain contractile function, and there is increasing evidence that energetic defects contribute to the development of heart failure. The last 10 years have seen a resurgent interest in cardiac intermediary metabolism and a dramatic increase in our understanding of transcriptional networks that regulate cardiac energetics. The PPAR-␥ coactivator ( Key Words: PGC-1 Ⅲ metabolism Ⅲ heart failure Ⅲ mitochondria T he heart consumes tremendous amounts of energy. ATP consumption, per weight of tissue, is the highest in the body. Energy reserves in the heart are relatively limited, and a heart starved of its fuel and oxygen supply can only beat 20 to 40 times (a few seconds) before succumbing to energy deficiency. Despite this narrow window, the healthy heart will contract billions of times in the average human life. The dynamic range of cardiac activity is large, both acutely (exercise) and chronically (development, especially postnatal). Bioenergetic programs in the heart must therefore be tightly regulated.ATP is the currency of energy in the cell. Oxidative consumption of fuels in mitochondria is by far the most efficient means of generating ATP, yielding Ͼ30 ATP per molecule of glucose, compared to a net 2 ATP via anaerobic glycolysis and lactate production. It is not surprising then that the heart is highly aerobic and sustains Ͼ95% of its ATP output via oxidative breakdown of fuels. Oxidative phosphorylation of ATP occurs strictly in mitochondria, and the heart therefore maintains a high mitochondrial content. The energetic requirements of the heart increase dramatically at birth, and mitochondrial density accordingly increases sharply during the perinatal period. 1-3 Mitochondrial mass makes up fully one-third of the adult heart.The PPAR-␥ coactivator (PGC)-1 transcriptional coactivators have recently emerged as powerful regulators of mitochondrial biology in the heart, by broadly regulating gene expression from both nuclear and mitochondrial genomes. The expression of PGC-1␣ is repressed in numerous models of heart failure, and this has been implicated as an important contributor to the maladaptive energetic profile of failing hearts. This review focuses on the PGC-1s and their role in cardiac biology. PGC-1 CoactivatorsCoactivators are proteins that bind to nuclear receptors or other transcription factors and increase their ability to stimulate transcriptional activity. Most transcription factors likely require coactivators. A subset of coactivators are highly regulated and transduce extra-and intracellular cues to Original

Skeletal muscle adapts to physiological demands by altering a number of programs of gene expression, including those driving mitochondrial biogenesis, angiogenesis, and fiber composition. Recently, the PGC-1 transcriptional coactivators have emerged as key players in the regulation of these adaptations. Many signaling cascades important in muscle physiology impinge directly on PGC-1 expression or activity. In turn, the PGC-1s powerfully activate many of the programs of muscle adaptation. These findings have implications for our understanding of muscle responses to physiological conditions like exercise, as well as in pathological conditions such as cachexia, dystrophy, and peripheral vascular disease.

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Summary Endothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1α is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1α expression is high in diabetic rodents and humans and that PGC-1α powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1α induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endothelial cells unresponsive to established angiogenic factors. Transgenic overexpression of PGC-1α in the endothelium mimics multiple diabetic phenotypes, including aberrant re-endothelialization after carotid injury, blunted wound healing, and reduced blood flow recovery after hindlimb ischemia. Conversely, deletion of endothelial PGC-1α rescues the blunted wound healing and recovery from hindlimb ischemia seen in type 1 and type 2 diabetes. Endothelial PGC-1α thus potently inhibits endothelial function and angiogenesis, and induction of endothelial PGC-1α contributes to multiple aspects of vascular dysfunction in diabetes.

(N Engl J Med. 2016;374:233–241) It is possible that peripartum cardiomyopathy is influenced by genetic factors, though this remains unclear. Similar to idiopathic dilated cardiomyopathy, this disease is associated with decreased systolic function, enlarged cardiac dimensions, and nonspecific histologic findings. These similarities are significant in that idiopathic dilated cardiomyopathy has been shown to be caused by a number of gene mutations. The authors of this study sequenced the DNA of 172 women suffering from peripartum cardiomyopathy to investigate whether there was a contribution from variants in the 43 genes known to be associated with dilated cardiomyopathy.