Titin truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ~1% of the general population where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout TTN were significantly associated with DCM. Ribosomal profiling in rat revealed the translational footprint of premature stop codons in Ttn, TTNtv position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-based analysis of high-resolution cardiac scans showed TTNtv to be associated with eccentric cardiac remodelling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease.

Although white adipocytes are best known as the cell type that sequesters large quantities of neutral lipid, most eukaryotic cells, including skeletal myocytes, form lipid droplets. Current interests in intramyocellular triacylglycerol (IMTG) stem largely from their infamous association with metabolic disease (reviewed in Refs. 1, 2 ). Thus, in the context of obesity and type 2 diabetes, IMTG content Abstract Intramuscular accumulation of triacylglycerol, in the form of lipid droplets (LD), has gained widespread attention as a hallmark of metabolic disease and insulin resistance. Paradoxically, LDs also amass in muscles of highly trained endurance athletes who are exquisitely insulin sensitive. Understanding the molecular mechanisms that mediate the expansion and appropriate metabolic control of LDs in the context of habitual physical activity could lead to new therapeutic opportunities. Herein, we show that acute exercise elicits robust upregulation of a broad program of genes involved in regulating LD assembly, morphology, localization, and mobilization. Prominent among these was perilipin-5, a scaffolding protein that affects the spatial and metabolic interactions between LD and their surrounding mitochondrial reticulum. Studies in transgenic mice and primary human skeletal myocytes established a key role for the exercise-responsive transcriptional coactivator PGC-1 ␣ in coordinating intramuscular LD programming with mitochondrial remodeling. Moreover, translational studies comparing physically active versus inactive humans identifi ed a remarkably strong association between expression of intramuscular LD genes and enhanced insulin action in exercisetrained subjects.These results reveal an intimate molecular connection between intramuscular LD biology and mitochondrial metabolism that could prove relevant to the etiology and treatment of insulin resistance and other disorders of lipid imbalance. Abbreviations: ATGL, adipose triglyceride lipase ; BMI, body mass index; DAG, diacylglycerol; EDL, extensor digitorum longus; EE, energy expenditure; G0S2, G0/G1 switch 2; HF, high fat; HSkMC, human skeletal myotube; IMCL, intramyocellular lipid; IMTG, intramyocellular triacylglycerol; NT, nontransgenic; LD, lipid droplet; PGC-1 ␣ , PPAR ␥ coactivator-1 ␣ ; PLIN5, perilipin family protein 5; PPAR, peroxisome proliferator-activated receptor; Rd, whole-body glucose disposal; ⌬ Rd, change in whole-body glucose disposal (insulin sensitivity); RQ, respiratory quotient; ⌬ RQ, change in respiratory quotient (metabolic fl exibility); SC, standard chow; SCD1, stearoyl-CoA desaturase 1; TA, tibialis anterior; TAG, triacylglycerol; VO 2 max, maximal oxygen consumption per kilogram of body weight as measured during maximal exercise test; Wmax, maximum watts achieved per kilogram of body weight as measured during a maximal exercise test.

ZBTB transcription factors orchestrate gene transcription during tissue development. However, their roles in glioblastoma (GBM) remain unexplored. Here, through a functional screening of ZBTB genes, we identify that BCL6 is required for GBM cell viability and that BCL6 overexpression is associated with worse prognosis. In a somatic transgenic mouse model, depletion of Bcl6 inhibits the progression of KrasG12V-driven high-grade glioma. Transcriptome analysis demonstrates the involvement of BCL6 in tumor protein p53 (TP53), erythroblastic leukemia viral oncogene homolog (ErbB), and MAPK signaling pathways. Indeed, BCL6 represses the expression of wild-type p53 and its target genes in GBM cells. Knockdown of BCL6 augments the activation of TP53 pathway in response to radiation. Importantly, we discover that receptor tyrosine kinase AXL is a transcriptional target of BCL6 in GBM and mediates partially the regulatory effects of BCL6 on both MEK-ERK (mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase) and S6K-RPS6 (ribosomal protein S6 kinase-ribosomal protein S6) axes. Similar to BCL6 silencing, depletion of AXL profoundly attenuates GBM proliferation both in vitro and in vivo. Moreover, targeted inhibition of BCL6/nuclear receptor corepressor 1 (NCoR) complex by peptidomimetic inhibitor not only significantly decreases AXL expression and the activity of MEK-ERK and S6K-RPS6 cascades but also displays a potent antiproliferative effect against GBM cells. Together, these findings uncover a glioma-promoting role of BCL6 and provide the rationale of targeting BCL6 as a potential therapeutic approach.

Brown adipose tissue (BAT) is specialized to burn lipids for heat generation as a natural defense against cold and obesity. Previous studies established microRNAs (miRNAs) as essential regulators of brown adipocyte differentiation, but whether miRNAs are required for the feature maintenance of mature brown adipocytes remains unknown. To address this question, we ablated Dgcr8, a key regulator of the miRNA biogenesis pathway, in mature brown as well as in white adipocytes. Adipose tissue–specific Dgcr8 knockout mice displayed enlarged but pale interscapular brown fat with decreased expression of genes characteristic of brown fat and were intolerant to cold exposure. Primary brown adipocyte cultures in vitro confirmed that miRNAs are required for marker gene expression in mature brown adipocytes. We also demonstrated that miRNAs are essential for the browning of subcutaneous white adipocytes in vitro and in vivo. Using this animal model, we performed miRNA expression profiling analysis and identified a set of BAT-specific miRNAs that are upregulated during brown adipocyte differentiation and enriched in brown fat compared with other organs. We identified miR-182 and miR-203 as new regulators of brown adipocyte development. Taken together, our study demonstrates an essential role of miRNAs in the maintenance as well as in the differentiation of brown adipocytes.

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