Hypertrophy
What is hypertrophy?
An increase in cell size which often leads to a concurrent increase in organ size and/or function.
Example of physiologic hypertrophy?
Gravid uterus This is a case of physiologic hypertrophy and hyperplasia of smooth muscles in the wall of the uterus in response to trophic factor estrogen associated with pregnancy. Compare the size of the normal uterus to that of a gravid uterus in the left image. Using fruit as a reference point, a normal uterus is about the size of a pear or an avocado. During the first trimester, it becomes a *grapefruit*, during the 2nd trimester a *papaya* and then a *watermelon* by the 3rd trimester. Microscopically, normal uterine smooth muscle cells have an ill-defined border, but have long spindle-shaped nucleus with very small nucleolus. The hypertrophied smooth muscle cells of the gravid uterus are large with recognizable cell outline and plump elongated nucleus with a nucleolus as indicated by red arrows. Distinguish? Appreciate that nuclei of normal uterus are very close together, indicative of narrow cell shape, whereas there's a marked increase in distance between nuclei of hypertrophied smooth muscle cells.
A healthy 40 year old man underwent a harvesting of a portion of his iliac crest bone grafting for correction of a maxillofacial defect. On the post-operative day 1 the patient developed femoral nerve damage that was shown to be consistent with muscle denervation due to prolonged compression of the femoral nerve during surgery. After several months of PT and rehabilitation the patient regained function of the injured limb. What cell mechanism best explains the patient's recovery?
Hypertrophy of the un-denervated muscle.
What are the clinical settings of hypertrophy?
Increased functional demand Increased trophic factors
3 important concepts to remember when it comes to changes in cell size as an adaptive cellular response?
1. Cells that are not capable of proliferating, such as skeletal and myocardial myocytes, undergo *hypertrophy* without proliferation; however, *hyperplasia* often accompanies hypertrophy of cells capable of proliferating. 2. Similarly, cells that are not capable of proliferating (skeletal and myocardial myocytes), undergo atrophy without apoptosis; however, apoptosis often accompanies atrophy of cells that are capable of proliferating. Cells capable of proliferating will respond to the addition of trophic factors by hyperplasia and hypertrophy, or when trophic factors are withdrawn they'll respond by apoptosis and atrophy. 3. Adaptive cellular changes are often reversible when the chronic stress of physiologic stimuli are removed. 2 pictures example: same person before and after training! Both hypertrophy and atrophy are seen. Body builder: skeletal muscle hypertrophy is associated with a physiologic increase in functional demand resulting from increased resistance (weight lifting) and is physiologic in nature. There's also concurrent atrophy of the adipose tissue (little body fat). The overweight man demonstrates atrophy of his skeletal muscle due to decreased functional demand as well as hypertrophy of adipose tissue due to trophic factor stimulation. Can see these concepts at work! Can't proliferate: hypertrophy and atrophy Can proliferate: hypertrophy/hyperplasia and atrophy/apoptosis
What is pathologic hypertrophy hypertension?
Compare the gross and microscopic images of normal heart (left) with that of heart from hypertensive patient (right). Increased functional demand is placed on myocardial muscle cells to pump blood through narrowed vessels in a setting of hypertension, leading to *myocardial cell hypertrophy* which is a *pathologic* process. However, hypertrophy MAY be physiologic in the case of exercise-induced hypertrophy. Pathologic hypertrophy of the myocardium of the LV is due to pumping against resistance. As one would expect, the larger heart is heavier and the left ventricular wall is thicker due to hypertrophy. Myocardial muscle cells of hypertrophic heart are much larger than those of normal heart. The small oval nuclei of the normal myocardial muscle cells are in contrast to the larger nuclei of the hypertrophied cardiac myocytes!
Mechanisms of hypertrophy?
Either mechanical stretch (increased workload), agonists (like alpha-adrenergic hormones, angiotensin) and growth factors (like IGF-1) can activate signal transduction pathways --> TF's (Myc, Fos, Jun, other). this can: - induce embryonic/fetal genes (cardiac alpha-actin, ANF) --> increased mechanical performance and decreased work load - increase synthesis of contractile proteins --> increased mechanical performance - increase production of growth factors (bind to receptor! ACTIVE process involving synthesis and degradation of cellular proteins.
A healthy 40 year old man underwent a harvesting of a portion of his iliac crest bone grafting for correction of a maxillofacial defect. On the post-operative day 1 the patient developed femoral nerve damage that was shown to be consistent with muscle denervation due to prolonged compression of the femoral nerve during surgery. After several months of PT and rehabilitation the patient regained function of the injured limb. An up-regulation of the fetal genes for which of the following proteins would most likely occur in the cells responding to the increased functional demand?
Myosin heavy chain
Example of pathologic hypertrophy?
Trophic signals -- anabolic steroids Oral: - anadrol, oxandrin, dianabol, winstrol Injectable: - deca-durabolin, durabolin, depo-testosterone, equipoise These steroids bind to nuclear receptors in skeletal muscle cells and activate TFs that stimulate fetal gene expression of contractile proteins and increase their synthesis. This leads to hypertrophy in patients taking them to increase muscle mass during weight training. These same drugs can induce skeletal muscle hypertrophy in settings associated with atrophy.