Phenotypic Modulation of Adult Tissues

Phenotype Plasticity

mature muscle has limited response to external signal (alter molecular composition and function)

hypertrophic growth (thickening—increase in protein per cell); hyperplastic growth (more cells)

cardiac terminally differentiated—not able to reproduce, only hypertrophy or dilation

proliferate only if E2F around; E2F only present if dissociated from Rb by CDK4/cyclin-D

p21 (produced from myogenin if not much CDK4/cyclin-D) stops this dissociation
cardiac muscle has little CDK4/cyclin-D, so Rb is bound to E2F, and terminal differentiation occurs

hypertrophy—response to increased pressure load, to normalize wall stress
dilation—response to increased vol load; narrowing – response to injury
not changes in size or shape—changes in gene expression (tissue changes at molecular level)

Potential Signalling Pathways to Produce Cardiac Hypertrophy (all increase Ca⁺⁺)

(1) serpentine G-protein (7-TM) (catecholamines (epi), angiotensin II, endothelin-1) activate PLC pathway; and/or tyr phos of IP₃

important to pharmacology (more effective than mechanical, such as diuretics/vasodilators)

(2) stretch-activated Ca⁺⁺ channels in sarcolemma

(3) one recent discovery (in skeletal muscle, but cardiac might be similar)

calmodulin binds phosphatase (calcineurin), that dephosphorylates NFAT (nuclear factor activator of transciption)
turns on hypertrophic genes (ANP, beta-MHC, alpha-actin)—only responds to sustained, low amplitude elevations in Ca⁺⁺level

(4) growth factor tyrosine kinases (TGF, FGF and SRF (serum response factor))

Phenotypic Modulation in Skeletal and Smooth Muscle: Fast-to-Slow Conversion

skeletal muscle: hypertrophic only (no replication), but can convert fast-to-slow

rapid stimulation: resting Ca⁺⁺ concentration 50 to 100-300 nM - myoglobin and TnI activated (probably by NFAT)
requires other regulators (e.g. MEF-2 (myocyte enhancing factor 2) in skeletal muscle, GATA in cardiac)

smooth: hypertrophy/dilate, but hyperplastic growth too (de-differentiation to replicate)

more known about hyperplasia than hypertrophy, because of atherosclerosis
fast to slow: factors like endothelin-1 increase resting Ca⁺⁺ concentration, suggest common mechanism

Functional Significance—hypertrophy switches muscle from fast-twitch to slow-twitch isoform

molecular adaptations to optimize performance (change preload, afterload, rate of contraction, etc.)

adult rodents high heart and metabolic rates due to "switch" (can reverse with AII or mechanical load)
human atria tuned to fast contractile isoforms, ventricles to slow

different isoforms of genes can increase contractile speed (occurs during embryo development to adult):

(1) more myosin light chain
(2) different tropomyosin and Tn-T isoforms that are less sensitive to Ca⁺⁺
(3) more SR Ca⁺⁺ ATPase
however the effect of hypertrophy is opposite (recapitulate to embryonic form) so less myosin light chain activity, Ca⁺⁺ sensitivity of thin filaments is increased, and Ca⁺⁺ cycled per contraction is decreased

Changes During Hypertrophy

excitation-contraction effects: more efficient at generating work, but not at high power (high hearth rate)

myosin ATPase reduced, Ca⁺⁺ sensitivity increased, and amount of Ca⁺⁺ cycled per contraction reduced

less SR Ca⁺⁺ ATPase, less SR Ca⁺⁺ release channels, more phospholamban, more Na⁺-Ca⁺⁺ exchanger

phosphorylation of Ca⁺⁺ pumps and channels, and thin filament regulatory proteins (TnI)
downregulation and uncoupling of cell surface receptors (beta andrenergic) and intersitial fibrosis

metabolic effects: cause faster ATP usage and glycolysis

more creatine kinase, less MCAD/LCAD (acyl CoA DH for FA metabolism), more glycolysis enzymes

Genetic Mutations—small percent of dilated or hypertrophic cardiomyopathies (sometimes inherited)

gene mutations in EC coupling:

usually mutation in myosin ATPase, sometimes in other prot (Tropomyosin or Tn-T)
some typical myosin mutations: all affect ATPases and actin translocation

mutations in metabolic enzymes:

MCAD defic causes fasting hypoglycemia, sudden death, and hypertrophic cardiomyopathy