Smooth muscle (SM) and striated muscle (SKM) are highly plastic, able to adapt their contractile properties in response to a variety of physiological settings such as exercise and pregnancy. Adaptations in these muscles involve coordinated changes in transcriptional rates of specific genes encoding contractile, metabolic and signal transduction proteins. In vascular SM (VSM), under normal physiological circumstances, plasticity infers tremendous benefit to vascular physiology; however, remodelling of VSM also underlies the pathology associated with various cardiovascular disorders including hypertension, pre-eclampsia, bronchospasm and vascular diabetic complications. Therefore it is necessity to define the pathways regulating VSM remodelling both in response to normal physiological settings as well as disease states. Adaptive changes in SKM also have physiological benefit. In humans, exercise training promotes switching of SKM to a more oxidative phenotype (Type2b-2a fiber switching). Since oxidative SKM is the major site of fatty acid oxidation, exercise induced changes improve physiological well-being and counter the development of Type 2 diabetes. Smoothelin-like protein 1 (SMTNL1) was first identified by our laboratory in SM as an early target of PKA and PKG in vivo. To fully understand the physiological role of SMTNL1 in vivo we developed the SMTNL1 null mouse (smtnl1-/-). Smtnl1-/- mice exhibit an exercise adapted phenotype both in terms of their VSM responses to Ca2+ desensitizing/sensitizing agonists, as well as, SKM fiber type content, strongly suggesting a role for SMTNL1 in the regulation of muscle plasticity. We also noted several sex related differences. Female smtnl1-/- mice exhibited greater adaptive changes than males and WT female mice expressed ~50% less SMTNL1 than males. More recently we found that expression of SMTNL1 is highly regulated during pregnancy and regulates expression of MYPT1 promoting Ca2+ desensitization in VSM. Strikingly, in detailed SKM fiber typing studies, we observed that pregnancy and SMTNL1 deletion induced fiber switching to a glycolytic phenotype in females. Additionally we obtained evidence that SMTNL1 mediates its remodelling effects in SM and SKM through direct interactions with the progesterone receptor (PR). Collectively our findings suggest that SMTNL1 is a master regulator of both SM and SKM remodelling during pregnancy as well as exercise. We hypothesize that remodelling events mediated through SMTNL1 may explain a number of physiological phenomena associated with pregnancy including pregnancy-induced hypotension as well as insulin-resistance.
SPECIFIC AIM 1 (Year 1-2). The molecular mechanisms by which SMTNL1 binds both MYPT1 and PRb in vitro and in vivo.
SPECIFIC AIM 2 (Year 2-3). The molecular mechanism by which SMTNL1 regulates PRb function to affect muscle plasticity in response to pregnancy in SM and SKM.
SPECIFIC AIM 3 (Year 3-5). In vivo studies on SMTNL1 phosphorylation and the role of the protein in mediating insulin resistance in pregnancy.
Remodeling of vascular smooth muscle enables the body to adapt to a variety of physiological settings such as exercise training or pregnancy. However, in certain pathological circumstances such as hypertension, pre-eclampsia, type II diabetes, asthma, restructuring of the muscle architecture has long-term detrimental effects. Understanding the molecular mechanism that normally govern smooth muscle remodeling may lead to the development of new therapies to prevent negative adaptive responses associated with these diseases.
| Bodoor, Khaldon; Lontay, Beata; Safi, Rachid et al. (2011) Smoothelin-like 1 protein is a bifunctional regulator of the progesterone receptor during pregnancy. J Biol Chem 286:31839-51 |
| Weitzel, Douglas H; Chambers, Jenica; Haystead, Timothy A J (2011) Phosphorylation-dependent control of ZIPK nuclear import is species specific. Cell Signal 23:297-303 |
| Borman, Meredith A; Freed, Tiffany A; Haystead, Timothy A J et al. (2009) The role of the calponin homology domain of smoothelin-like 1 (SMTNL1) in myosin phosphatase inhibition and smooth muscle contraction. Mol Cell Biochem 327:93-100 |
