Effect of GW-501516 and AICAR on muscle

[johnjuanb1]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482394/


Effect of GW and AICAR on muscle weight and behavioral activity measures
The average body mass of the treated mice was significantly higher than that of vehicle-treated mice (Figure ​(Figure2A).2A). Treatments increased the body mass by ~10% (GW, 9.2%; AICAR, 11.3%; GW&AICAR, 10.63%). A general increase in the weight of the EDL, gastrocnemius, quadriceps, soleus, and TA muscles was found in the drug-treated groups (statistically significant for the quadriceps (GW, +12.7%; AICAR, +14.6% ; GW&AICAR, 13.7%) (Figure ​(Figure2B)2B) and soleus (GW, +14.3%; AICAR, +17.4%) (Figure ​(Figure2C).2C). Interestingly, abdominal fat was decreased in response to all three treatments (Figure ​(Figure2D),2D), and the decrease was statistically significant for both single-treatment groups.
Grip strength and open-field animal activity tests were performed before and after drug treatment. We found a significant increase in forelimb grip strength in the GW501516-treated and combination-treatment groups (Figure ​(Figure2E,F).2E,F). The increase in hind limb grip strength was significant for all three treatments (Figure ​(Figure2G).2G). Since these drugs influenced body weight, we normalized data to body weight. Both forelimb and hind limb grip strength increased significantly with GW501516 (+19%, +13%, respectively) and combination treatment (+25%, +13%, respectively) (Figure ​(Figure2F).2F). Behavioral activity measures did not significantly change for the single treatments but the combination treatment group showed significantly increased movement time (89%) (Figure ​(Figure2I)2I) and decreased rest time (Figure ​(Figure2J),2J), suggesting an overall beneficial effect on these parameters.

 

[johnjuanb1]

The most controversial reported side effect of GW is increased cancer incidence. The one animal study that showed this, out of many studies on Cardarine, used a dose one hundred times larger than the normal dose for over 10 times as long as the research chemical is typically used. This “side effect” is highly disputed. More in-depth studies have found that Cardarine actually reduces tumor size.

That study was crap. Resent research shows GW-501516 is being used to kill cancer cells. I posted these studies in the GW-501516 thread here.

 

[johnjuanb1]

Apoptotic effect of the selective PPARβ/δ agonist GW501516 in invasive bladder cancer cells.
Péchery A, et al. Tumour Biol. 2016.

Abstract

GW501516 is a selective and high-affinity synthetic agonist of peroxisome proliferator-activated receptor β/δ (PPARβ/δ). This molecule promoted the inhibition of proliferation and apoptosis in few cancer cell lines, but its anticancer action has never been investigated in bladder tumor cells. Thus, this study was undertaken to determine whether GW501516 had antiproliferative and/or apoptotic effects on RT4 and T24 urothelial cancer cells and to explore the molecular mechanisms involved. Our results indicated that, in RT4 cells (derived from a low-grade papillary tumor), GW501516 did not induce cell death. On the other hand, in T24 cells (derived from an undifferentiated high-grade carcinoma), this PPARβ/δ agonist induced cytotoxic effects including cell morphological changes, a decrease of cell viability, a G2/M cell cycle arrest, and the cell death as evidenced by the increase of the sub-G1 cell population. Furthermore, GW501516 triggered T24 cell apoptosis in a caspase-dependent manner including both extrinsic and intrinsic apoptotic pathways through Bid cleavage. In addition, the drug led to an increase of the Bax/Bcl-2 ratio, a mitochondrial dysfunction associated with the dissipation of ΔΨm, and the release of cytochrome c from the mitochondria to the cytosol. GW501516 induced also ROS generation which was not responsible for T24 cell death since NAC did not rescue cells upon PPARβ/δ agonist exposure. For the first time, our data highlight the capacity of GW501516 to induce apoptosis in invasive bladder cancer cells. This molecule could be relevant as a therapeutic drug for high-grade urothelial cancers.

 

[johnjuanb1]

**broken link removed**

Therapeutic potential of GW501516 and the role of Peroxisome proliferator-activated receptor β/δ and B-cell lymphoma 6 in inflammatory signaling in human pancreatic cancer cells

Abstract

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a member of the nuclear receptor superfamily and a ligand-activated transcription factor that is involved in the regulation of the inflammatory response via activation of anti-inflammatory target genes and ligand-induced disassociation with the transcriptional repressor B-cell lymphoma 6 (BCL6). Chronic pancreatitis is considered to be a significant etiological factor for pancreatic cancer development, and a better understanding of the underlying mechanisms of the transition between inflammation and carcinogenesis would help further elucidate chemopreventative options. The aim of this study was to determine the role of PPARβ/δ and BCL6 in human pancreatic cancer of ductal origin, as well as the therapeutic potential of PPARβ/δ agonist, GW501516. Over-expression of PPARβ/δ inhibited basal and TNFα-induced Nfkb luciferase activity. GW501516-activated PPARβ/δ suppressed TNFα-induced Nfkb reporter activity. RNAi knockdown of Pparb attenuated the GW501516 effect on Nfkb luciferase, while knockdown of Bcl6 enhanced TNFα-induced Nfkb activity. PPARβ/δ activation induced expression of several anti-inflammatory genes in a dose-dependent manner, and GW501516 inhibited Mcp1 promoter-driven luciferase in a BCL6-dependent manner. Several pro-inflammatory genes were suppressed in a BCL6-dependent manner. Conditioned media from GW501516-treated pancreatic cancer cells suppressed pro-inflammatory expression in THP-1 macrophages as well as reduced invasiveness across a basement membrane. These results demonstrate that PPARβ/δ and BCL6 regulate anti-inflammatory signaling in human pancreatic cancer cells by inhibiting NFκB and pro-inflammatory gene expression, and via induction of anti-inflammatory target genes. Activation of PPARβ/δ may be a useful target in pancreatic cancer therapeutics.