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Monthly Archives: August 2012
Exercise training vs Muscle gaining and loss….
How can we built muscle? How do we lose it????
Looking into several degenerative muscular diseases ( Cancer, Diabetes, Heart Disease, Hypertension….) that will progressively deteriorate muscle and organs, whether due to lifestyle choices such as exercise or eating habits, it has been shown that exercise training exerts beneficial effects on skeletal muscle. Furthermore, it has been shown that the expression of myostatin, a key regulator of skeletal muscle mass, is increased in a variety of cachectic states.
Because of its high prevalence and association with several diseases,
muscle wasting is a significante clinical problem. To address it more effectively, a thorough understanding of the underlying molecular pathways is crucial.
WHAT CAN LEAD TO MUSCLE LOSS?
Many mechanisms: Increase the levels of neuroendocrine mediators like (nor)epinephrine, angiotensin II, or proinflammatory cytokines….. Simplifying: Every time that we stimulate our sympathetic nervous system (SNS) we induce a catabolic state in the muscle. The myostatin was identified as an important mediator of muscle wasting. Myostatin acts in an endocrine fashion to communicate to skeletal muscle and induce atrophy. This protein is:
1)Natural regulatory protein
2)Member of TGF-b family
3)Inhibits muscle growth
4)Increases with age
5)An evolutionary circuit breaker to keep muscle growth in check
Probably inhibits recruitment of muscle stem cells
In the picture we can see that Myostatin is recognize by membrane receptors, such as ActRIIB. But it can also be inhibited by other molecules such as Follistatin. Exercise training increases follistatin concentration in the blood and muscle is free to grow without myostatin inhibitor effect. Hard exercise training can increase follistatin in the blood above 50%.
So in disease or in good health, we must think about this molecular pathways to understand «the effort (exercise) is a gain or a lost»
Why do Our tissues and organs stop to grow? From simple stem cells into different organs…..
Animals have rapid body growth in early life stages, then the body impose limits to itself. From a single stem cell, several differente tissues (hearth, skin, eyes…) differentiate and acquire differente functions.
WHY… What promotes differentiation? Stimulus or inhibitiors?
Recent studies and (Julian C. et al, 2011) provide insight into a long-standing this mystery of biology.
So until now, we know that here are several mechanisms involved. This mechanisms act locally and not in a systemic way. Of course that behind this control there is a genetic map where the inhibitor information is primarly imprinted. So there are several genes that are responsible for new proteins once expressed in tissues, limit the growth.
In my study, i looked for hearth and muscle growth… Imagine that skeletal and cardiac muscle growth are negatively regulated by myostatin and the concentration depends on muscle mass itself. Liver growth appears to be modulated by bile acid flux, a parameter that reflects organ function. In pancreas, organ size appears to be limited by the initial number of progenitor cells, suggesting a mechanism based on cell-cycle counting. Further elucidation of the fundamental mechanisms suppressing juvenile growth is likely to yield important insights into the pathophysiology of childhood growth disorders and of the unrestrained growth of cancer.
In addition, improved understanding of these growth-suppressing mechanisms may someday allow their therapy.
Growth-suppressing mechanisms may someday allow their therapeutic suspension. Maybe, in HAP we will be able to stop Smooth muscle cells to proliferate in vessels.
Changes in blood vessel diameter can stop blood flow… What controls it?
In smooth muscle cell, there are key mediators of the proliferative effect… so the vessel has several walls that can proliferate without any control.
WHAT? PROLIFERATE LIKE A CANCER? YES
Several substances stimulate smooth muscle cell growth and induces oxidative stress.
Oxidative stress is a specific cellular crisis, that can disturb normal cell rules. Oxidative stress is started by ROS (reactive oxigen species). When intracellular ROS production in endothelial cells increases, smooth muscle starts to proliferate.
Other factors are related with this proliferation: MMP (matrix metalloproteinases). MMP are capable of degrading all kinds of extracellular matrix proteins associated with smooth muscle matrix cell proliferation and migration. MMP is expressed abundantly in atherosclerotic lesions and plays an important role in increasing VSMC (vessel smooth muscle cells). MMP react with inter cell matrix allowing individual cell migration.
SO… ROS allow proliferation while MMP allow migration…. we can say that «CAOS» BEGAN… Lúmen vessel get smaller and blood find a big obstacle to his passage.
In summary, the proliferative effects of ET-1 (endothelial cells) involves an increase in the production of ROS. Further study of the signaling pathways involved may identify additional points at which ET-1-induced proliferation can be inhibited. Because antioxidants and other these agents may be of benefit in preventing the SMC proliferation associated with pulmonary vascular diseases.
Myocardin and Smooth muscle differenciation in Hypertension
Myocardin was shown to be a specific transcription factor that plays a central role in smooth muscle differentiation….Using several assays, we could show that the myocardin is lost at the point where slow growing cells are converted into fast growers we also found that myocardin expression is essential for their differentiation (Milyavsky et al., 2007). The unique contractile properties of the SMC lineage are directed by SRF/myocardin-regulated genes encoding SMC-restricted contractile proteins…. In the next picture we can see how this differentiation happends:
The fibroblast (immature cell)when exposed to a Growth factor (TGF-β1) increases assembly of a muscle filament called F-actin, inducing the myocardin-related transcription factor (MRTF)-A/B to go into the nucleus. After enter the nucleos, MRTF binds to serum response factor (SRF), and promote expression of a contractile gene program…. Program? yes, a group of other proteins tha regulate gene cell muscle differentiation. This group is called CArG-containing genes and the members are α-actin (SMαA), SMγA, SM22-α, h1-calponin, and vinculin. The expression of these genes causes changes to the cytoskeleton, resulting in differentiation of the myofibroblast and the development of contractile function…. so this is another way to keep studying how smooth muscle proliferates in lung vessels… is essencial to understand how this happens to keep looking for a therapy to hypertension.