SUMMARY Skeletal muscle atrophy is a common and debilitating condition that lacks a pharmacologic therapy. To develop a potential therapy, we identified 63 mRNAs that were regulated by fasting in both human and mouse muscle, and 29 mRNAs that were regulated by both fasting and spinal cord injury in human muscle. We used these two unbiased mRNA expression signatures of muscle atrophy to query the Connectivity Map, which singled out ursolic acid as a compound whose signature was opposite to those of atrophy-inducing stresses. A natural compound enriched in apples, ursolic acid reduced muscle atrophy and stimulated muscle hypertrophy in mice. It did so by enhancing skeletal muscle insulin/IGF-I signaling, and inhibiting atrophy-associated skeletal muscle mRNA expression. Importantly, ursolic acid’s effects on muscle were accompanied by reductions in adiposity, fasting blood glucose and plasma cholesterol and triglycerides. These findings identify a potential therapy for muscle atrophy and perhaps other metabolic diseases.

Prolonged fasting alters skeletal muscle gene expression in a manner that promotes myofiber atrophy, but the underlying mechanisms are not fully understood. Here, we examined the potential role of activating transcription factor 4 (ATF4), a transcription factor with an evolutionarily ancient role in the cellular response to starvation. In mouse skeletal muscle, fasting increases the level of ATF4 mRNA. To determine whether increased ATF4 expression was required for myofiber atrophy, we reduced ATF4 expression with an inhibitory RNA targeting ATF4 and found that it reduced myofiber atrophy during fasting. Likewise, reducing the fasting level of ATF4 mRNA with a phosphorylation-resistant form of eukaryotic initiation factor 2alpha decreased myofiber atrophy. To determine whether ATF4 was sufficient to reduce myofiber size, we overexpressed ATF4 and found that it reduced myofiber size in the absence of fasting. In contrast, a transcriptionally inactive ATF4 construct did not reduce myofiber size, suggesting a requirement for ATF4-mediated transcriptional regulation. To begin to determine the mechanism of ATF4-mediated myofiber atrophy, we compared the effects of fasting and ATF4 overexpression on global skeletal muscle mRNA expression. Interestingly, expression of ATF4 increased a small subset of five fasting-responsive mRNAs, including four of the 15 mRNAs most highly induced by fasting. These five mRNAs encode proteins previously implicated in growth suppression (p21(Cip1/Waf1), GADD45alpha, and PW1/Peg3) or titin-based stress signaling [muscle LIM protein (MLP) and cardiac ankyrin repeat protein (CARP)]. Taken together, these data identify ATF4 as a novel mediator of skeletal myofiber atrophy during starvation.

APPROXIMATELY 300,000 patients undergo cardiac surgical procedures each year in the United States. More than 80% of routine cardiac surgical procedures are performed using cardiopulmonary bypass (CPB).1 Acute kidney injury (AKI; previously referred to as acute renal failure) after CPB is a well-known, yet incompletely understood, entity that has significant implications on both short-and long-term outcomes. The development of AKI after CPB is associated with a significant increase in infectious complications, an increase in length of hospital stay, and greater mortality when compared with patients without AKI-CPB.2 The incidence of AKI-CPB averages 20 -30%, depending on the definition used and the duration of the postoperative period studied.3,4 Furthermore, more patients with AKI-CPB who require dialysis remain dialysis dependant. For all patients undergoing CPB, the risk of AKI-CPB is the least in those who undergo coronary artery bypass grafting (CABG) only; the risk increases for patients undergoing valve replacement surgery; and the risk is the greatest after combined CABGvalve procedures. 4 There has not been a significant reduction in mortality, despite many recent advances in our understanding of the causative pathophysiology and pharmacotherapeutics of AKI-CPB. Furthermore, advances in renal replacement therapies (RRTs) have not significantly altered the overall mortality associated with AKI-CPB.In this review, we will focus on the current definitions of AKI, pathophysiologic features, and risk factors for developing AKI-CPB. We will also discuss perioperative strategies and emerging concepts that add to our understanding of this complex entity to help better manage patients at risk for AKI-CPB. Defining AKIAKI is a complex diagnosis and has been described using several definitions and diagnostic criteria, ranging from a 25% increase in baseline serum creatinine (sCr) to the need for hemodialysis.3,4 The requirement for a consensus definition addressing early detection and grading of severity of AKI led to the development of the Risk-Injury-Failure-Loss-End stage kidney disease (RIFLE) classification by the Acute Dialysis Quality Initiative. 5 To further refine the scoring, the Acute Kidney Injury Network (AKIN) proposed a modification of the RIFLE classification, known as the AKIN classification. 6 The RIFLE and AKIN classifications have been used and validated in prospective studies 7 in patients with AKI after cardiac surgery.The differences between RIFLE and AKIN staging criteria are subtle. Stage 1 in the AKIN classification has been broadened to include patients with an increase in sCr of at least 26.5 M (0.3 mg/dl) greater than baseline because there is accumulating evidence that even minor increments in sCr concentration are associated with adverse outcomes. 6 In contrast, the "risk" stage of RIFLE classification requires a 50% increase in sCr over baseline. Urine output over time is retained in both classification systems because it may precede the increase in sCr, especially in critically ill ...

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Introduction In humans, spinal cord injury (SCI) induces deleterious changes in skeletal muscle that may be prevented or reversed by electrical stimulation muscle training. The molecular mechanisms underlying muscle stimulation training remain unknown. Methods We studied two unique SCI subjects whose right soleus received >6 years of training (30 minutes/day, 5 days/week). Results Training preserved torque, fatigue index, contractile speed and cross-sectional area in the trained, but not the untrained leg. Training decreased 10 mRNAs required for fast twitch contractions and mRNA that encodes for myostatin, an autocrine/paracrine hormone that inhibits muscle growth. Conversely, training increased 69 mRNAs that mediate the slow twitch, oxidative phenotype, including PGC-1α, a transcriptional co-activator that inhibits muscle atrophy. When we discontinued right soleus training, training-induced effects diminished slowly; some persisted >6 months. Discussion Training of paralyzed muscle induces localized and long-lasting changes in skeletal muscle mRNA expression that improve muscle mass and function.

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The ubiquitin proteasome pathway plays a key role in cell cycle, function and survival. Bortezomib (BTZ) and Carfilzomib (CFZ) are the first two inhibitors of the proteasome pathway, indicated in treatment of patients with multiple myeloma. In the past few years, there have been few case reports that have highlighted the association between proteasome inhibitors (BTZ and CFZ) with acute kidney injury (AKI). In most of these case reports and initial trials, the underlying mechanism of AKI has been unclear. In this article, we discuss the association and pathogenesis of proteasome inhibitors-associated AKI. We also report the first case of CFZ-associated AKI with kidney biopsy evidence of thrombotic microangiopathy and the presence of microangiopathic hemolytic anemia.

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