Effect of exercise training on the FNDC5/BDNF pathway in spontaneously hypertensive rats.

Increased sympathetic activity contributes to the development of cardiovascular diseases such as hypertension. Exercise training lowers sympathetic activity and is beneficial for the prevention and treatment of hypertension and associated cognitive impairment. Increased BDNF expression in skeletal muscle, heart, and brain may contribute to these actions of exercise, but the mechanisms by which this occurs are unknown. We postulated that hypertension is associated with decreased hippocampal BDNF, which can be restored by exercise-mediated upregulation of fibronectin type-II domain-containing 5 (FNDC5). Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were subjected to 5 weeks of motorized treadmill training. BDNF and FNDC5 expressions were measured in the left ventricle (LV), quadriceps, soleus muscle, and brain areas. Exercise training reduced blood pressure (BP) in both strains. BDNF and FNDC5 protein in the LV were increased in SHR, but exercise increased only BDNF protein in both strains. BDNF mRNA, but not protein, was increased in the quadriceps of SHR, and BDNF mRNA and protein were decreased by exercise in both groups. FNDC5 protein was higher in SHR in both the quadriceps and soleus muscle, whereas exercise increased FNDC5 protein only in the quadriceps in both strains. BDNF mRNA was lower in the dentate gyrus (DG) of SHR, which was normalized by exercise. BDNF mRNA expression in the DG negatively correlated with BP. No differences in FNDC5 expression were observed in the brain, suggesting that enhanced BDNF signaling may contribute to the cardiovascular and neurological benefits of exercise training, and these processes involve peripheral, but not central, FNDC5.

A specific FMNL2 isoform is up-regulated in invasive cells.

BACKGROUND: Formins are a highly conserved family of cytoskeletal remodeling proteins. A growing body of evidence suggests that formins play key roles in the progression and spread of a variety of cancers. There are 15 human formin proteins and of these the Diaphanous-Related Formins (DRFs) are the best characterized. Included in the DRFs are the Formin-Like proteins, FMNL1, 2 & 3, each of which have been strongly implicated in driving tumorigenesis and metastasis of specific tumors. In particular, increased FMNL2 expression correlates with increased invasiveness of colorectal cancer (CRC) in vivo and for a variety of CRC cell-lines in vitro. FMNL2 expression is also required for invasive cell motility in other cancer cell-lines. There are multiple alternatively spliced isoforms of FMNL2 and it is predicted that the encoded proteins will differ in their regulation, subcellular localization and in their ability to regulate cytoskeletal dynamics. RESULTS: Using RT-PCR we identified four FMNL2 isoforms expressed in CRC and melanoma cell-lines. We find that a previously uncharacterized FMNL2 isoform is predominantly expressed in a variety of melanoma and CRC cell lines; this isoform is also more effective in driving 3D motility. Building on previous reports, we also show that FMNL2 is required for invasion in A375 and WM266.4 melanoma cells. CONCLUSIONS: Taken together, these results suggest that FMNL2 is likely to be generally required in melanoma cells for invasion, that a specific isoform of FMNL2 is up-regulated in invasive CRC and melanoma cells and this isoform is the most effective at facilitating invasion.