ADAPTATIONS OF CELLULAR GROWTH AND DIFFERENTIATION Adaptations are reversible changes in the size number phenotype metabolic activity or functions of cells in response to changes in their environment Such adaptations may take several distinct forms Hypertrophy 1 is an increase in the size of cells that results in an increase in the size of the affected organ 2 The hypertrophied organ has no new cells just larger cells 3 The increased size of the cells is due to the synthesis and assembly of additional intracellular structural components 4 Cells capable of division may respond to stress by undergoing both hyperplasia and hypertrophy whereas nondividing cells e g myocardial fibers increase tissue mass due to hypertrophy 5 In many sites hypertrophy and hyperplasia may coexist with both contributing to increased organ size 6 Hypertrophy can be physiologic or pathologic the former is caused by increased functional demand or stimulation by hormones and growth factors 7 Pathologic hypertrophy The striated muscle cells in the heart and skeletal muscles have only a limited capacity for division and respond to increased metabolic demands mainly by undergoing hypertrophy 8 The most common stimulus for hypertrophy of skeletal and cardiac muscle is increased workload 9 In both tissue types muscle cells respond by synthesizing more protein and increasing the number of myofilaments per cell 10 work capacity of the muscle as a whole 11 overload usually resulting from either hypertension or valvular disease 12 the stage for heart failure and other significant forms of heart disease 13 Physiologic hypertrophy The massive physiologic growth of the uterus during pregnancy is a good example of hormone induced enlargement of an organ that results mainly from hypertrophy of smooth muscle fibers 14 estrogen receptors that eventually result in increased synthesis of smooth muscle proteins and an increased cell size 15 individual skeletal muscle fibers in response to increased demand 16 Mechanisms of Hypertrophy Hypertrophy is a result of increased cellular protein production This in turn increases the amount of force each myocyte can generate and thus the strength and Initially cardiac hypertrophy improves function but over time this adaptation often fails setting A classic example of pathologic hypertrophy is enlargement of the heart in response to pressure Uterine hypertrophy during pregnancy is stimulated by estrogenic hormone signaling through The bulging muscles of bodybuilders engaged in pumping iron result from enlargement of These and other pathways activate transcription factors including GATA4 nuclear factor of Cardiac hypertrophy is also associated with a switch in gene expression from genes that encode Much of our understanding of hypertrophy is based on studies of the heart There is great interest in defining the molecular basis of myocardial hypertrophy because beyond a Hypertrophy results from the action of growth factors and direct effects on cellular proteins Mechanical sensors in the cell detect the increased load These sensors activate a complex downstream web of signaling pathways including the 17 18 certain point it becomes maladaptive 19 20 21 phosphoinositide 3 kinase PI3K AKT pathway postulated to be most important in physiologic e g exercise induced hypertrophy and G protein coupled receptor initiated pathways activated by many growth factors and vasoactive agents and thought to be more important in pathologic hypertrophy 22 Some of the signaling pathways stimulate increased production of growth factors e g TGF insulin like growth factor 1 IGF1 fibroblast growth factor and vasoactive agents e g adrenergic agonists endothelin 1 and angiotensin II 23 activated T cells NFAT and myocyte enhancer factor 2 MEF2 which increase the expression of genes that encode muscle proteins 24 adult type contractile proteins to genes that encode functionally 25 replaced by the isoform which has a slower more energetically economical contraction 26 participate in the cellular response to stress 27 expression 28 blood volume and pressure and therefore serves to reduce hemodynamic load 29 Whatever the exact cause and mechanism of cardiac hypertrophy it eventually reaches a limit beyond which enlargement of muscle mass is no longer able to cope with the increased burden 30 At this stage several regressive changes occur in the myocardial fibers of which the most important are degradation and loss of myofibrillar contractile elements 31 32 adaptation to stress can progress to functionally significant cell injury if the stress is not relieved In extreme cases myocyte death can occur The net result of these changes is cardiac failure a sequence of events that illustrates how an Atrial natriuretic factor is a peptide hormone that causes salt secretion by the kidney decreases distinct fetal isoforms of the same proteins For example the isoform of myosin heavy chain is Other proteins that are altered in hypertrophic myocardial cells are the products of genes that For example cardiac hypertrophy is associated with increased atrial natriuretic factor gene