PGC1β activates an antiangiogenic program to repress neoangiogenesis in muscle ischemia

Revascularization of ischemic skeletalmuscle is governed by a balance between pro- and antiangiogenic factors in multiple cell types but particularly in myocytes and endothelial cells. Whereas the regulators of proangiogenic factors are well defined (e.g.,hypoxia-inducible factor [HIF]), the transcriptional pathways encoding antiangiogenic factors remain unknown. We report that the transcriptional cofactor PGC1β drives an antiangiogenic gene program in muscle and endothelial cells. PGC1β transcriptionally represses proangiogenic genes (e.g., Vegfc, Vegfd, Pdgfb, Angpt1, Angpt2, Fgf1, and Fgf2) and induces antiangiogenic genes (e.g., Thbs1, Thbs2, Angstat, Pedf, and Vash1). Consequently, musclespecific PGC1β overexpression impairs muscle revascularization in ischemia and PGC1β deletion enhances it. PGC1β overexpression or deletion in endothelial cells also blocks or stimulates angiogenesis, respectively. PGC1β stimulates the antiangiogenic genes partly by coactivating COUP-TFI. Furthermore, roangiogenic stimuli such as hypoxia, hypoxia-mimetic agents, and ischemia decrease PGC1β expression in a HIF-dependent manner. PGC1β is an antiangiogenic transcriptional switch that could be targeted for therapeutic angiogenesis

Multi-disciplinary efforts to evaluate the therapeutic potential of CDK11, a novel transcription associated cyclin dependent kinase.

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Muscle Arnt/Hif1β Is Dispensable in Myofiber Type Determination, Vascularization and Insulin Sensitivity

<div><p>Aryl Hydrocarbon Receptor Nuclear Translocator/ hypoxia-inducible factor 1 beta (ARNT/ HIF1β), a member of bHLH-PAS family of transcriptional factors, plays a critical role in metabolic homeostasis, insulin resistance and glucose intolerance. The contributions of ARNT in pancreas, liver and adipose tissue to energy balance through gene regulation have been described. Surprisingly, the impact of ARNT signaling in the skeletal muscles, one of the major organs involved in glucose disposal, has not been investigated, especially in type II diabetes. Here we report that ARNT is expressed in the skeletal muscles, particularly in the energy-efficient oxidative slow-twitch myofibers, which are characterized by increased oxidative capacity, mitochondrial content, vascular supply and insulin sensitivity. However, muscle-specific deletion of ARNT did not change myofiber type distribution, oxidative capacity, mitochondrial content, capillarity, or the expression of genes associated with these features. Consequently, the lack of ARNT in the skeletal muscle did not affect weight gain, lean/fat mass, insulin sensitivity and glucose tolerance in lean mice, nor did it impact insulin resistance and glucose intolerance in high fat diet-induced obesity. Therefore, skeletal muscle ARNT is dispensable for controlling muscle fiber type and metabolic regulation, as well as diet-induced weight control, insulin sensitivity and glucose tolerance.</p></div

ARNT expression in different tissues.

<p><b>(A)</b> ARNT protein expression in different organs [sub-cutaneous adipose tissue (Sc), perigonadic adipose tissue (Pg), brown adipose tissue (Bat), heart (He), liver (Li), brain (Br), kidney (Ki), pancreas (Pa), gastrocnemius muscle (Ga)] of 4 months old mice (N = 1). <b>(B)</b> Arnt gene expression in the soleus and the extensor digitorum longus (EDL) of 3 month old mice (N = 4–5). <b>(C-D)</b> ARNT expression in control and MKO muscle groups ranging from the most oxidative (soleus) to most glycolytic (EDL) (N = 3). (C) Representative images. (D) Densitometry for protein expression. (E) Arnt gene expression in EDL control and MKO muscles of 4 months old mice (N = 4–5). (*p<0.05,**p<0.01,***p<0.001, Unpaired Student’s t-test or One-way ANOVA with Tukey’s multiple comparison post-hoc test.)</p

Insulin and Glucose Tolerance.

<p>Following parameters were measured in control and MKO mice on HFD. (A) Weight gain (N = 6–12). (B) Fat mass in 4 month old mice (N = 6–12). (C) Lean mass in 4 month old mice (N = 6–12). (D) Insulin tolerance test (ITT) in 4 months old mice (N = 6–11). (E) Area Above the Curve (AAC) for ITT. (F) Glucose tolerance test (GTT) in 4 months old mice (N = 6–11). (G) Area Under the Curve (AUC) for GTT. (H) Ex vivo p-AKT ser473/panAKT stimulation by insulin measured in the gastrocnemius muscles of the 5 months old mice (N = 3–5). $indicates the treatment effect; * indicate the genotype effect.$ p<0.05; $$ $/*** p<0.001 (Unpaired Student’s t-test or Two-way ANOVA with a Bonferroni’s repeated measure test).</p

Exercise and PGC-1 alpha-Independent Synchronization of Type I Muscle Metabolism and Vasculature by ERR gamma

SummaryHow type I skeletal muscle inherently maintains high oxidative and vascular capacity in the absence of exercise is unclear. We show that nuclear receptor ERRγ is highly expressed in type I muscle and, when transgenically expressed in anaerobic type II muscles (ERRGO mice), dually induces metabolic and vascular transformation in the absence of exercise. ERRGO mice show increased expression of genes promoting fat metabolism, mitochondrial respiration, and type I fiber specification. Muscles in ERRGO mice also display an activated angiogenic program marked by myofibrillar induction and secretion of proangiogenic factors, neovascularization, and a 100% increase in running endurance. Surprisingly, the induction of type I muscle properties by ERRγ does not involve PGC-1α. Instead, ERRγ genetically activates the energy sensor AMPK in mediating the metabovascular changes in ERRGO mice. Therefore, ERRγ represents a previously unrecognized determinant that specifies intrinsic vascular and oxidative metabolic features that distinguish type I from type II muscle