Atrophy

Chronic increased pressure? Examples?

*Hydrocephalus* and the formation of *decubitus ulcers* (= pressure ulcer, pressure sore) are classic examples of chronic pressure induced atrophy. Hydrocephalus is associated with increased CSF in the cerebral ventricles due to an obstruction. If the obstruction is not corrected, the increased pressure will dilate the ventricles, causing atrophy of the surrounding cerebral tissue! "Unhappy looking" brain CT scan with enlarged ventricles! Decubitus ulcers (bedsores) represent atrophy of the skin/subcutaneous tissue overlying bony prominences, commonly the sacrum, ankles, knees, elbows. They arise due to chronic pressure on the tissue because of a lack of movement. Categorized according to stages that are defined by depth. The ulceration may be superficial or it can extend deep to the bone itself! They can be prevented by reducing the pressure and turning the patient. Stage I is best, redness. Stage II has thickening of dermis, III is worse, IV is worst.

Hypoplasia vs aplasia?

*Hypoplasia* is incomplete development of tissue or of an organ with reduced cell numbers. *Aplasia* is absence of tissue or an organ or failure to develop. Hypoplasia is NOT atrophy!!! Response = hyperplasia (if R kidney hypoplasia, L kidney hyperplasia!)

Clinical settings of atrophy?

- Decreased functional demand. - Decreased oxygen supply (*hypoxia*) -- often associated with ischemia, decreased blood supply to tissue - Starvation or malnutrition - Decreased trophic factors -- denervation or reduced trophic factor stimulation - Persistent cell injury (chronic pressure, chronic inflammation, chronic disease, aging) Trophic factors = hormones or other growth factors.

3 types of autophagy?

1. *Chaperone-mediated autophagy* -- involves a direct *translocation* of specific, cytoplasmic, soluble proteins bound to a chaperone protein (Hsc70 and 73) to a receptor protein on the lysosomes. The translocated proteins are rapidly degraded by the lysosomal enzymes. VERY specific. 2. *Microautophagy* -- is a nonspecific degradation of cytoplasmic constituents. It involves invagination of the lysosome membrane around cytoplasmic material that then pinches off to form an internal vacuole in which the material is hydrolyzed by the lysosomal enzymes. 3. *Macroautophagy* -- involves sequestering portions of the cellular cytoplasm and organelles in a double-membrane bound vesicle called *autophagosome*, which then fuses with the lysosome. Like microautophagy, macroautophagy is a *nonselective* degradation pathway; however, it can selectively damage endoplasmic reticulum, mitochondria and peroxisomes. Macroautophagy, commonly referred to as autophagy, begins with the formation of a C-shaped double-membrane structure in the cytosol (*phagophore*) that elongates to engulf the cytoplasmic components and closes to form a vacuole (*autophagosome*). The outer membrane of the autophagosome fuses with the lysosomal membrane and the inner membrane (the autophagic body) carrying the cytosolic constituents enters the lysosome and is degraded by the lysosomal enzymes.

What is cachexia? What is it mediated by?

A significant skeletal muscle and adipose tissue atrophy independent of nutritional intake. Negative protein balance and increased glucose utilization due to elevated adrenergic state. >50% of cancer patients have it at the time of death. Negative impact of cancer treatment! Mediated by *cytokines*: *IL-6, TNF-alpha, PIF (proteolysis inducing factor)*. Cachexia is the hallmark of progressive diseases. May be associated with patients with TB, AIDS, amphetamine addiction, and in >50% of cases of cancer. Loss of body mass due to significant atrophy of skeletal muscle/adipose tissue independent of nutritional intake. Cancer cachexia in Hubert Humphrey who had bladder cancer. Cancer cachexia is associated with a negative protein balance and increased glucose utilization due to elevated adrenergic state. Result: significantly increased rate of carbohydrate metabolism. Somatic skeletal muscle is the primary site of lean body mass depletion due to increased rate of protein turnover without appropriate increase in protein synthesis! Cancer cachexia mediated by cytokines secreted by tumor and stromal cells. They induce digestion: protein-ubiquitination-proteasome activity and autophagy.

Weight loss with increased resistance exercise would most likely cause atrophy of which one of the cell types.

Adipocytes (Yes. Exercise induced lipolysis will lead to atrophy not apoptosis of adipocytes.)

Chronic inflammation? Example?

Atrophy due to chronic inflammation is best seen in the case of *chronic gastritis* -- inflammation of the stomach lining. In normal gastric epithelium, the double headed arrow demonstrates the thick epithelial layer with the numerous branching tubular glands that are close to each other! Little CT between the glands! In atrophic gastritis, the glands (blue) are small in size and few in number. The reduction in number is due to cell death due to apoptosis. Emphasize: *atrophy and apoptosis go hand-in-hand!* The space between the atrophied glands is widened and filled with little dark dots which are *lymphocytes, plasma cells, and macrophages* (green arrows). Acute gastritis on the right. Shows the progression! Compare the thickness of the epithelial layers in A and D. Image A is early gastritis without glandular atrophy and a normal thickness of the epithelium. Image D demonstrates a significant loss of glands, with inflammatory cells expanding the widening spaces between the glands, and marked thinning of the epithelial layer. The white arrows indicate that aggregates of inflammatory cells are in the epithelium. They're localized in early gastritis, but fill much of the epithelial layers in chronic gastritis.

What is atrophy?

Atrophy refers to a decrease in cell size and function with concurrent decrease in organ size and/or function. It may be accompanied by cell death (apoptosis).

A 21 year-old male developed marked weight loss and loss of muscle mass secondary to an eating disorder. Which one of the following mechanisms would most likely account for the muscle changes?

Autophagy (Yes - reduced nutrition leads to autophagy!) Necrosis = NO because this is starvation not ischemic injury/trauma. Hypertrophy = NO because this is the opposite of atrophy. Apoptosis = NO because this atrophy is due to loss of muscle MASS, not muscle cells.

Decreased oxygen supply? What does this result from/lead to?

Decreased oxygen supply to tissue often results from decreased *blood flow* to the tissue. This *ischemia* (= inadequate blood supply to an organ/part of body) is often due to *atherosclerosis* (= a disease of the arteries characterized by the deposition of plaques of fatty material on their inner walls). If this narrowing of the blood flow is chronic in nature, the slow decline in oxygen supply will induce atrophy rather than cell death. Ex: right kidney atrophic due to chronic narrowing of renal artery due to atherosclerosis at its origin. The left kidney is *hypertrophied* in response to the increased physiologic demand resulting from a decreased functional right kidney.

What do cells of normal skeletal muscle versus atrophic skeletal muscle look like?

Ex: limb is immobilized, so you get atrophy of the skeletal muscle. Seen in casting of limb, prolonged bedrest, inactivity. Decrease in the inactive leg's diameter and amount of muscle. "disuse atrophy" In the image, you can tell there's increased ECM between skeletal muscle cells! In NORMAL muscle cells, there's little ECM. Increase in ECM between atrophied myocytes compared to the normal skeletal muscle myocytes.

Describe the diagram regarding changes in cell from homeostasis?

Normal cell (homeostasis) encounters injurious stimulus. This leads to cell injury. If it's an intense, acute stimulus, this leads to cell death: *apoptosis, necrosis, necroptosis*. If it's a mild/transient stimulus, this leads to reversible injury, which can put the cell back towards normal. Sometimes under chronic stress after cell injury or due to physiological stimulus, the cell undergoes adaptation which leads to changes in cell size (*intracellular accumulation, cell number, cell differentiation*). Note: nonphysiologic = injurious. Changes in cell size and/or differentiation may or may not be reversible!

During stress induced atrophy, which one of the following requires ubiquitination prior to degradation of unwanted cytoplasmic proteins?

Proteasome digestion (Yes - Polyubiquitination of proteins is required for proteasome degradation.) Chaperone-mediation autophagy (No - This process is specific and only requires chaperone-bound proteins) Macroautophagy (No - This is nonspecific lysosomal degradation of organelles) Microautophagy (No - This is nonspecific lysosomal degradation of cytoplasmic constituents including proteins)

How do you remove unwanted organelles/proteins?

Proteasome digestion and autophagy! Atrophy is an active process that involves both a decrease and an increase in the synthesis of various proteins. However, destruction of unwanted organelles and proteins is an essential mechanism for cell shrinkage. Some proteins can be removed by proteasome digestion (think paper shredder). Proteasome removal of unwanted proteins *requires ubiquitination*, without it the proteins will accumulate. Remember: proteasome activity is a normal function of cell homeostasis and not just a response to atrophy. *Requires ATP!* Autophagy is a pathway for degradation of cytoplasmic organelles and molecules that leads to recycling of the molecular building blocks. This self-cannibalization occurs when cells are *under stress leading to a deprivation of nutrients*. It's associated with normal turnover of organelles and cytoplasmic aggregates as well as cell death that is *distinct* from necrosis and apoptosis.

Cerebral atrophy?

Results from decreased oxygen supply, too! There are several mechanisms that lead to cerebral atrophy. *Chronic cerebral ischemia* secondary to *small vessel disease* is one of these causes. The normal brain has an "angry cat" appearance and the CT of the atrophic brain has a "jowly" appearance. Cerebral atrophy is associated with *enlarged lateral ventricles* as compared to their normal counterparts, as well as increased size of sulci between the gyri and overall shrinkage away from the frontal bone at the anterior lobes of the brain.

Decreased nutrition?

Severe deficiency in caloric intake may lead to atrophy: lack of resources or eating disorder. Starvation is a severe deficiency in caloric intake. This severe type of malnutrition could also be the result of an eating disorder as seen with anorexia nervosa. In these cases, energy is preferably derived from *carbs*, then *fat*, then *muscle protein*. The extent of skeletal muscle atrophy during starvation depends on the amount of energy stores the body has at the beginning of starvation and the length of starvation. This is also the case with anorexia! Muscle atrophy is reversible with adequate nutrition.

Decreased trophic stimulation? Examples?

These two cases demonstrate atrophy due to decreased trophic stimulation. This is commonly encountered when a nerve to skeletal muscle is cut or from the loss of hormonal or growth factor stimulation of normally responsive cells and tissue. Note the asymmetry of the woman's face. Cutting of CNVII (facial nerve) caused denervation of facial muscles (red arrow) that is clinical referred as Bell's palsy. Early stages of denervation are characterized by scattered small (atrophic) angulated fibers (black arrows). With time the atrophic fibers form groups (group atrophy - dotted line). Those skeletal muscle fibers that remain innervated will undergo compensatory hypertrophy. Compare the two right hand images of endometrium. The upper image is that of normal proliferative endometrium under the control of estrogen stimulation. To the right of the dashed black line is a thick endometrium with numerous, tall, straight glands that branch as they get deeper. In contrast, endometrial atrophy is seen when estrogen stimulation is lost during menopause. In the lower image, above the dotted line is the thin atrophic endometrium with its few glands. The removal of trophic stimulation leads not only to cellular atrophy but also to cell death via apoptosis.