Exam 4 Flashcards
Outer membrane vs. inner membrane of Mitochondria
Outer: very porous; folded proteins can pass through channels; General Import Pores
Inner: very tight; site of oxidative phosphorylation where generation of proton gradient exists; Tim23 and Tim22
General Import Pores
transports folded proteins
N terminal of protein has positive leader sequences that binds to negative inside of channel
Facilitated diffusion and ATP independent!
Tim23 and Tim22
found on inner mitochondrial membrane
very tight channel to protect proton gradient
Gated channels
Positive N terminus binds to outside and protein gets transported inside.
Protein is unfolded and plugs whole to prevent loss of proton gradient.
Hsp70 binds to unfolded protein and uses ATP hydrolysis to make a kink and pull protein in the channel
Fission - mito
Drp1 and Bax facilitate the pinching off and division of mitochondria
Fusion
Mfn and OPA mediate fusion of mitochondria
how many calories are made with each ATP to ADP conversion?
7.3 kcal/mol
NADH structure
Two pentose rings hooked by two phosphates
an adenosine head
Oxidized form of NADH
NAD
Reduced form of NADH
NADH
Oxidative phosphorylation
Glucose is broken into two pyruvates (3C) that occurs in lack of oxygen to make 2 ATP
Pyruvate moves to mito and diffuses across outer membrane where it goes into the TCA cycle to break down into CO2, 3 NADH, and 1 FADH.
Electron Transport Chain
NADH donates electron and gets oxidized to pump protons outside.
one NADH transfers 5 protons out and forms 1 water
ATP Synthase
driven by proton gradient
protons run through channel and phosphorylate ADP to ATP.
single glucose gives 22 ATP
ATP synthase conformations
ADP and pi
brings ADP and Pi together
Looses affinity to ATP
How is apoptosis induced in mito
by activation of cytochrome c
Cytochrome c
usually involved in oxidative phosphorylation (complex IV)
CytoC binds to form an apoptosome that signals to activate caspases.
How is apoptosomes regulated?
reducing or oxidizing cytochrome C by NADH
all healthy cells form apoptosomes, but cell changes mind if the cell has the energy to reverse the activation of cyto c.
if the cell is lacking energy, cyto C cannot be inactivated and drives to apoptosis.
Quality Control in Mitochondria
Molecular: set of proteins that detect oxidative phosphorylation enzymes that are defective and degrades them
Mitophagy: degrade the piece of mito that is defective
Apoptosis: kills the cell all together
Molecular quality control in Mito:
mAAA are proteins that detect mutations in Oxidative phsophorylation enzymes and degrades them.
Lots of mutations associated with these: hereditary spastic paraplegia.
Primary Cilia
Microtubule extension out of PM on apical surface
senses physical and biochemical environment
a 9+0 arrangement
signaling and NOT motile
Motile Cilia
used when movement of fluid is required
respiratory, neural, and reproductive
2 extra MT in center of axonomes
central pair
the extra two MT in axonemes that give the motile cilia a characteristic 9+2 arrangement
Components of cilia
Basal Body anchor Transition Zone Axeneme scaffolding Intraflagellar transport Outer Ciliary Membrane
Basal Body
anchor to the axoneme structure - incredibly stable
derived from centrosome
200nm by 500 nm
central hub with radiating modified microtubules in TRIPLET
9 subunits; 3 MT per subunit
Axoneme
scaffold structure in cilia
DOUBLET MT with central pair of MTs which makes the m more stable than singlets.
Nexin
the linker between doubles in cilia to ensure integrity
How to cilia move?
dynein arms grab onto neighboring subunits and cause a pulling force that leads to motility
Intraflagellar transport
Active mechanism that regulates which components can enter and move down the cilia through the transition zone.
Bidirectional trafficking mechanism in cilia
Proteins/vesicles must have a localization signal very similar to control of nuclear pore.
Transition Zone
the linkage domain or gatekeeper of cilia
links basal body to axoneme
ensures that proteins and membranes components of cilia are distinct from PM
contains Alar Sheets
mutated in ciliopathies
what is analogous to nuclear pore in cilia
alar sheets in the transition zone
limit cytoplasmic and diffusible proteins from entering
what stage does ciliogenesis occur
G0 or G1
First step in ciliogenesis
basal bodies from centrioles migrate to surface of cell and attach to rich cortex.
along the way they associate and fuse with ciliary membrane vesicles that fuse with plasma membrane
elongation of cilia
once at Plasma membrane, basal body nucleates outcroth of axoneme
what forms the transition zone of the cilia
distal regions of the basal body
maintenance of cilia
proteins synthezied in cyto are transported via IFT
tubulin continues to be incorportated at the tip, but cilia does not elongate further.
What drives movement to the + end in cilia?
Kinesin 2 and IFT-B
This is the end of the cilia
what drives movement to the - end of cilia?
Dynein-2 and IFT-A
returns to the base of the cilia
Basal body formations
derived from centrioles and are typically formed during cell replication.
Mother centrioles are associated with ciliogenesis
New centrioles always develop at the base of the mother centriole.
How are multi-ciliated cells made?
Must be differentiated cell
Bypass the once and only once duplication of DNA and centrioles, to make multiple centrioles.
Forms dueterosome and all migrate to build cilium structure
deuterosome
used in multi-ciliary cells and help recruit machinery to build cilia
1) daughter centriole supports procentriole nucleation via deuterosome formation.
2) deuterosomes are released into cytoplasm
3) centriole growth from deutersosome
4) centriole release and maturation for docking cilia growth
Physical benefits of Cilia
Concentration of signal localized polarized fluid mechanics charge disruption flow sensing
concentration of signal - cilia
cilia create microenvironment for signaling with high surface receptor to volume ratio
How are cilia flow sensing
mechanical bending senses fluid flows
Receptors in Cilia detect
physical stimuli, light, chemical stimuli ( hormones, chemokines, GFs, morphogens)
Result of ciliary signaling
cell proliferation, motility, polarity, growth, differentiation, tissue maintenance
Sonic Hedgehog pathway - unstimulated
PTCH1 is on surface of cilia and Gli is respressed by SUFU
SMO is sequestered to intracellular vesicle
Sonic Hedgehog pathway - stimulated
Hh binds and causes PTCH1 to no longer be on surface cilia membrane and for SMO to translocate to cilia surface
This causes Cli to be transported to tip of cilia and represses SUFU to cause activation of GliA.
GliA is transported by dynein into cytoplasm and nucleus to become TF.
Hh Signaling effects..
Limb formation - growth, digit number, polarity
Bone formation: cell proliferation, diff, growth
Neurogenesis: neural tube formation, differentiation, cell migration
Left right axis formation and cilia
gastrulation establishes anterior and posterior
Ciliary pits beat in a rotary fashion at 600 bpm at the proper angle to generate net leftward flow. This causes asymmetry of growth factors and biochemical signals.
Depends on the primary cilia to sense the mechanical flow.
Characteristics of Ciliopathies
1) Rare
2) pleiotropic
3) most affect structural elements of cilia
4) Diverse range of mutations - most occurring in transition zone
5) genetically complex
6) phenotypes overlap
Bardet-Biedl Syndrome
Mutation in gene that encodes basal body proteins in cilia
affects vesicular trafficking, MT anchor, and IFT
AR disorder
pathology: photoreceptor degradation, mental retardation, kidney defects, asomnia, obesity, diabetes
Polycystic Kidney Disease
AD and AR both exist
1:1000 (maybe more)
mutation in polycystin1 and 2
pathology: renal cysts, renal failure and liver and pancreatic cysts, intracranial aneuryisms
Polycystin 1 and 2
mutated in PKD
channel proteins located at cilia base, just above transition zone.
sense mechanical urine flow to signal for Ca release to induce proliferation and cystogenesis
Function of epithelial
barrier, absorption and transport, secretion, movement though passageways, biochemical modification, sensory reception, communication
endothelium
epithelial cells that line the blood and lymph vessels
mesothelium
epithelial that encloses internal spaces of the body cavity
Vasculature in epithelium
avascular
no direct blood supply, nutrient and oxygen
diffuse through CT, BL to reach epithelial cells
Formation of epithelium
begins with primitive epithelium, which is just a single sheet of cells.
derived from endo, meso, and extoderms
these cells receive morphogenetic signals for transformation that causes disassembly and reformation during various parts of development in uterus.
some detach and migrate to become mesenchymal
this process stops at birth but is hyper-activated in cancer
Mucosae
epithelia in most internal linings
has outer epithelium
lamina propria: CT directly under eptihelia
submucosa: deep CT
Simple vs Stratified epithelia
simple: single sheets
stratified: multiple sheets
Squamous vs. cuboidal vs. columna
squamous: outer layer is flat (long but short)
cuboidal: cube shaped
columnar: tall cells
Pseudo-stratified Epithelia
all cells remain in contact with BL, but not all reach free surface
Transitional epithelia
stratified, but histologically look like a single layer
found in bladder
Function of epithelial polarity
unidirectional secretion or absorption
transcytosis
transport of vesicles in epithelia that is unidirectional - movement though the cell
Apical surface specializations
Microvilli and Cilia
Microvilli
located on apical surface.
extension of actin that increase surface area.
Stereocilia is most common: found in epididymis and in ear.
Basolateral specializations
lack structural organization
still has folds to increase surface area
Tight Junctions
Zonula Occludens
uses claudins and occludins
appear like a belt surrounding cells
Limit paracellular transport and promote Transcellular transport.
work intracellularly to regulate cyto proteins that monitor gates
Adhearence Junctions
Zona Adherens
Cadherins that connect to actin skeletal
cadherins recruit kinases and phosphatases to regulate gene expression control cell division and polarity
Desmosomes
also use cahderins, but bind to Intermediate filaments
Promote structural integrity of epithelium
mutations cause blistering
Gap Junctions
actual channels that promote rapid communication between the cells through channels.
allow flow of ions, second messengers.
Non-specific!
Basal Lamina Components
collagen, glycoproteins, laminins, entactin
high variable depending on cell type.
Function of Basal lamina
epithelial attachment, selective filtration, polarity, highways for migration, barrier to invading materials, control gene expression, tissue scaffolding
Attachments to basal lamina
Hemidesmosomes and Focal Adhesions
Hemidesmosomes
link internally with integrins to intermediate filaments and provide structural connection.
Focal Adhesions
use integrin to attach to actin cytoskeleton.
have signaling capabilities to provide role in polarity
Exocrine Glands
secretes from apical surfaces of epithelia
multicellular
begin as sheet of epithelia that invaginates and elongates but remains connected as it grows.
Contains Acini that flow into the ducts
Acini
secretory units in exocrine glans that are located at the base and secrete into the ducts.
Endocrine glands
secrete hormones into bloodstream from BL side
start with primitive epithelium that invaginates, but there is a detachment from the apical surface.
Hormones must travel through BL of gland and then through another BL of the vessel to get into bloodstream
Transit Amplifying cells
intermediates in the process of differentiation of epithelial cells.
these cells have a shortened lifespan to divide rapidly and then differentiate.
much faster than stem cells.
WNT pathway in colon
WNTs are secreted ligands that bind to receptors to regulate downstream protein that regulates beta-catenin to stimulate cell division and inhibits differentiation.
APC
ACP inhibits B-catenin by sequestering it in the nuclues
WNT 7A
when gene expression of WNT7a is increased, associated with loss of function of APC in colon cancer, but not lung!
Decreased WNT-7s is not associated with colon cancer, but it is associated with Lung cancer.
WNT7A in lung
WNT7A acts on beta catenin to inhibit cell division and promote differentiation.
Cadherin and squema cell carcinoma
1) mutations in cadherin disrupt junctions in eptihelial to make more migratory
2) change in signaling pathways to change gene expression
3) it could be that low Cadherin is the effect of squema carcinoma and not the cause…
what binds to the antigen
the variable region
what gins to the antibody
the epitope
Superficial Fascia
CT near body surface with lots of fat; easily dissected
Deep Fascia
tougher deeper region of CT
Prominent thick epimysium (outer covering of muscles) and ligaments, tendons, joint capsules.
Connective Tissue Function
Mechanical strength, regulation of nutrient and metabolism between organs and blood vessels, control behavior and function of cells contacting ECM
Types of CT
Resident and Immigrant
Resident CT
produce and secrete ECM and proliferate to produce new CT
mesenchymal, fibroblasts, myofibroblasts, Adipocytes, osteoblasts, osteocytes, chondorcytes, smooth muscle
Mesenchymal cells
Resident CT
the precursors to all CT found primarily in embryogenesis
high telomerase activity
give rise to fibroblasts
Fibroblasts
Resident CT
pre-eminent cells in most CT
synthesizes fibrous proteins, proteogycans, and ECM components
capable of cell division
Sensory and proliferation is highly regulated - scarring is hypertrophy of fibroblasts
many different types of fibroblasts depending on cell type.
Can transform into variety of CT (adipocytes, Smooth muscle, chondrocytes, osteoprogenitors) - though this has not been proven in live human cells.
Myofibroblasts
Resident CT
derived from fibroblasts, capable of smooth muscle like function
Found at wound sites to contribute to retraction and shinkage of scar tissue.
Adipoctyes
Resident CT
fibroblasts derivatives or primitive mesenchymal
store fat and energy
Brown Fat: found in newborns with many mito to convert FA into heat.
Chondrocytes
Resident CT
cells that make cartilage
Immigrant blood derived CT
originate from precursors circulating in blood;
produced form hematopoietic cells in marrow and migrate into blood and CT
acct as part of immune system
Lymphocytes, macrophages, neurophils, esosinophils, mast cells, osteoclasts
Lymphocytes
immigrant CT
acquired immunity
Macrophages
immigrant CT
phagocytose cells, ECM, and non-cellular material
stimulate angiogenesis, remove damage tissue, remodel normal developing tissue
Neurophiles and eosinophils
immigrant CT
defense against microoorganisms
Mast Cells
immigrant CT
secretory, release vasodilators to promote swelling
Osteoclasts
immigrant CT
derived from blood monocytes
promote bone resorption and remodeling
Structural aspects of ECM
Collagen, Elastic fibers
Collagen
fibrous proteins that form aggreage fibers
triple helix
many different types due to alpha chain
Fibrillar collagen
large bundles of collagen fibrils
collagen alighned head to tail to generate long strands.
provides tensile strength
(collagen I)
Fibril-Associated collagen
decorate surface of collagen fibrils
linke collagen fibrils together or to the BL
(Collagen 4)
Network Forming Collagen
think and assemble into interlaced networks
form porous cheets
Forms basal lamina, anchors BL and cells to ECM, filtration barriers in kidney
Loose Connective Tissue
thick collagen fibrils that are sparse
irregular lattice network with high cell density and ground substance, blood and lymph, nerves
Dense connective tissue
thick collagen that are more abundant
irregular or parallel arrangements for greath strength and to resist force.
ligaments and tendons
Collagen syntehsis
synthesized and modified intracellularly and exported for further modification
Intracellular collagen synthesis
peptide synthesis in ER lumen, post-trans modification by glycoslyation and hydroxylation, forms triple helix in golgi
Extracellular collagen synthssis
N and C are cleaved by specific proteases
release of N-telo peptides cause formation of bundles and end to end polymers; crosslinks are formed to increase tensile strength
N-Telo peptides
fragments created with extracellular processing of collagen.
high levels in blood or urine due to a Connective Tissue disease
Elastic Fibers
elastin and fibrillin
create resiliency when stretched and relaxation when released
propels blood through capillaries and arteries
Elastin
filamentous, random coil conformation
fibroblasts secrete monomers and form extracellular filaments and sheets with numerous cross links
Fibrilin
is interwoven in elastin to help form a fiber
Ground substance
hydrated gelatinous material that surrounds structural elements
Proteoglycans are most responsible.
Proteoglycans
protein core with large acidic GAGs
highly negative charge *hydrophilic
binds to both active and inactive proteins
Elements of ground substance
Proteoglycans, proteases that process collagen and proteins, growth factors and polypeptide ligands, inorganic and small organic solutes
General Steps of Wound healing
Inflammation and clotting; Proliferation /New tissue formation; Tissue remodeling
Inflammation and clotting - wound healing
ruptured tissues release platelets into connective tissue and activates them to produce blood clots that temporarily seal wound.
fibroblasts, mast cells, and macrophages release signals to increase water permeability, increase cellular permeabile to monoctyes, lymphocytes, and blood cells, attract migration of white cells, stimulate fibroblasts and differentation of monocytes into macrophages
Hitamine
released during inflammation and clotting by mast cells to promote endothelial permeabilization
signal to hematopoietic tissue to stimulate WBC production
cytokines - wound healing
secreted by white blood cell derivatives and by fibroblasts
signal to hematopoietic tissue to stimulate WBC production
Proliferation/New Tissue Formation in wound healing
fibroblasts divide and secrete ECM components
signals trigger division and differentiation of epithelial; ECM proliferation and remodeling; macrophages trigger angiognesis, repair and remodeling
Tissue remodeling in would healing
the ECM, cellular composition, and structure of CT, epithelium are altered depending on wound location and severity
cellularity (density of cells) is reduced; ECM is thinner, imperfect remodeling forms scar tissue
chronic inflammation is hallmark of which diseases…
ulcerative collitis, Crohns, rheumatoid arthritis, stomach ulcers, skin disorders
Function of bone and cartilage
mechanical support; attachment of muscles and joints, protection of organs, regualtion of calcium homeostasis, housing of homeoploitic tissue
Bone characteristics
highly dynamic - constant turnover and rebuilding
highly vascularized
maintaisn precursor cells capable of cell division and differentiation into bones.
Cartilage characteristics
must less dynamic than bones
avascular in matrix
limited ability to repair in adults
converted to bone in adults
Cartilage Function
resilient but pliable structure
direct formation and growth of bone
retained in teh trachea, nasal passage, ear, intervertebral discs, ribs, skull, and tendons
Where is cartilage located in adults?
only on articular surfaces
Chondrocytes
cells that make the cartilage matrix and tissue
differentiated from sheet of primitive mesenchymal stem cells
Perichondrium
external layer of CT that surrounds cartilage; thin but dense
promotes and maintains growth; gives rise to chondrocytes
Chondrocytes during growth…
proliferate and secrete componentes of ECM. As they surround themselves they isolate themselves in the Lacuna.
Chondroblasts
proliferative chondrocytes, (essentially chondrocytes but in cell division.
when growth is completed, they chondrocytes withdraw from cell cycle and retain capability to secrete cartilage matrix, but at lower rates.
Hyaline Cartilage
collagen with relatively thick fibrils
irregular 3D pattern
rich in proteoglycans and hyaluronic acid (protein free GAG) to promote hydration and flexibility.
Hyaline Cartilage ECM
metabolites readily diffuse
promotes resiliency to compressive force during joint movement
allows growth of condorcytes and matrix from within matrix
calcifies during growth
Elastic Cartilage
thick collagen fibrils and proteoglycans
abundance of elastic fibers and intrconnecting sheets of elastic material
found in external ear, epiglottis, larynx
matrix does not calcify
Fibrocartilage
bundles of regularly arranged collagen that is similar to dense CT
hybrid between dense CT and cartilage
resists compression and shear force
where tendons attach to bone and in intervertebral discs
Types of cartilage matrix
hyaline, elastic, fibrocartilage
Formation of cartilage
mesenchymal cells divide and differentiate into chondrocytes.
Chondrocytes secrete matrix and individual chondorcytes become encase in a lacuna.
How does cartilage growh?
apposition and interstital
appositional growth of cartilage
growth on surface
perichondrium, mesenchymal and fibroblasts proliferate and differentiate into chondrocytes to secrete matrix.
upward thickening
Interstitial growth of cartilage
growth form within
chondrocytes within matrix proliferate within lacunae and secrete ECM.
cellular division in lacuna.
Periosteum
compact bone made out of fibroblasts
outer region of the bone
Spongy bone
also called cancellous and trabecular.
inner portion of bone with thick anastomosing spicules called trabeculae.
purpose of trabeculae
surface area for metabolism; hold bone marrow
White bone marrow
adipose cells
Endosteum
spongy bone that stores and mobilizes calcium
Osteoprogenitor
mesenchymal stems calls whose daughters become osteoblasts and osteocytes
present in both perosteal and endosteal surfaces
Osteoblasts
line inner lining of both periosteal and endosteal surfaces where bone growth and remodeling occurs.
secrete osteoid
pinch of matrix vesicles
capable of cell division
Matrix vesicles
contains enzymes that initiate bone calcification
Osteocytes
derivatives of osteoblasts; form as they become surrounded and encased by bone matrix.
arrested in G0
use canaliculi for communication
don’t secrete matrix, but modify and sense matrix to send signals for regualtion
canaliculi
long tiny channels that allows for communication of osteocytes with surrounding matrix
Osteoclasts
derived from monocytes in blood or hematopoietic stem cells.
Resemble macrophages: perform phagocytosis and angiognesis
degrade bone to allow inward growth of blood vessels and nerves
Resorb bone for purpose of mobilizing Ca into blood stream.
Bone Matrix
ECM of bone is calcified and pack with collagen
contains negative proteoglycans
contains large amounts of crystallized Ca and PO4 called hydrozyapatite to make mineralized matrix
Haversian Canals
long bones that traverse the long axis through compact bone
Volkmann’s Canal
link haversian canals to each other and to the perisoteum at bone surface
intramembranous ossification
used for flat bone formation
done in absence of pre-made cartilage.
condensation of mesenchymal in loose connective tissue to form osteoprogenitors and eventually osteoblasts.
Osteoblasts secrete osteoid
relatively delay/slow bone formation process
osteoid
secreted by osteoblstasts
unmineralized ECM of bone
Cartilage bone model
for long bones
cartilage condenses in CT and forms long bone structure.
Endochondral ossification occurs within bone formation
bone grows intersitially and appositionally
1) pericondrum is converted to perisoteum
2)mesenchymal cells swithc from chondrocytes to bone lineage
3) osteoblasts secrete matrix into cartilage cuasing them to recruit osteoclasts and degrade calcified cartialge and bring with then N and blood vessels.
4) in internal spaces osteoblasts secrete bone matrix
Site of ossification of long bones
diaphysis and grows outward to epiphysis
how does a bone grow in length
at the epiphyseal plate
requires cartilage cells
occurs alongside interstitial growth at growth plate
Osteoblast vs osteoblast and calcium
Osteoclast mobilize calcium; osteoblast: deposit calcium
what pathways control bone formation
short range signals, long range signals, mechanical stress, neuronal stimulation
Short rage bone signals
same pathways as epithelial development
Sonic Hedgehog, notch TBGB
Fibrodisplaysia Ossificans Provecevia
is a disorder in which muscle tissue and connective tissue such as tendons and ligaments are gradually replaced by bone (ossified), forming bone outside the skeleton (extra-skeletal or heterotopic bone) that constrains movement
Fibrodisplaysai ossificans provecevia mechanism
genetic translocation of BMP4 is linked to lymphocyte promoter.
When this is hyperactive, it inapproprately produces signal that acts on mesenchymal cells and fibroblasts to convert osteoblast progenitors into osteoblasts
Long range bone signals
parathyroid hormone stimulates Ca release and bone resorption
Calcitonin: decreases Ca release and stimulate bone deposition
General Vasculature structure
Tunica Intima, Tunica media, tunica adventitia
Tunica Intima:
innermost layer of vessel; endothelial cells contacting blood
layers of elastic and loose collagenous tissues
always sqaumous to allow for effective diffusion of O2 and CO2.
not most effective transport for glucose and AA
Tunica Media
middle of vessles
composed of multiple layers of elastic lamina and smooth muscle and collagen
Tunica Adventitia
outer supporting layer, collagenous tissues
contains vasa vasorum and nervi vascularis
How is artery thickness related?
thick wall is determined by medial layer.
thickness decreases from heart to arterioles.
Large Artery/Aorta Structure
Intima: inner layer of endothelial cells and some connective tissue
Media: inner elastic lamina; multiple layers of smooth muscle, outer layer of elastic lamina
adventitia: elastic and strong CT.
what is the inner elastic lamina made of?
collagen and elastin rich fibers
Small muscular arterioles
contain intima, media, and adventitia.
Loose outer lamina, but remain inner.
Venules vs Arterioles
venules lack layers of smooth muscles because they dont’ control blood flow as much..
Arterioles vs. Lymphatics
mostly of squamous layer, but not much smooth mucles
Athlerosclerosis
builds up and elaboration of intima that makes lumen smaller
Arterial venous shunts
control blood flow into capillary bed
contraction: prevents blood flow into capillary, but relaxation promotes flow into capillary.
larger than metarterioles
metarterioles
control blood flow into capillaries using pre-capillary sphincter that lead directly into capillary bed.
Capillary stucture
single endothelail cell lining; basal lamina surrounding.
Pericyte wraps partically around it within CT
Pericyte
cell that is wrapped partially around the capillaries.
involved in repair and angiogenesis upon damage
How does fluid get into capillaries?
pincytotic vesicles
Fenostrated endothelial cells
discontinous endothelium
Pinocytotic vesicles
small amount of fluid that is transported across cytoplasm in small vesicles.
Fenostrated endothelial cell
holes in endothelial cells that permit bulk flow of fluid
present in kidney and liver
filtration still occurs via basal lamina
Discontinuous Endothelium
allow red blood cells and leykocytes to pass
seen in spleen and is important in immune responses and taking red blood cells out of blood.
How does histamine influence permeability of vessles?
between endothelial cells.
diapedesis
process by which leukocytes leave blood by working their way through epithelial wall between cells.
Leukocytes in bone marrow get into blood within 8-10 hours
Adeventitia
can have vasa visorum as you increase in vein size
Varicose veins are due to..
valve failure
Skeletal muscle characteristics
Large 50-100 um diameter, multi-nucleated in periphery, striated, No gap junctions
Cardiac Muscle
smaller than skeletal, striated, large in diameter but short fibers, Interacalated discs, nucleus located centrally
Intercalated discs
borders cardiac myocyte..
Adheres cells together in transverse region
gap junctions promote electrical signal propagation in lateral regions
Smooth Muscle Characteristics
Single nucleus, thin diameter of 2-5 um, spindle shaped with nucleus near center, contain different actin and myosin organization
Muscle Fascicle
In anatomy, a muscle fascicle is a bundle of skeletal muscle fibrils surrounded by perimysium, a type of connective tissue.
myofibril
A myofibril (also known as a muscle fibril) is a basic rod-like unit of a muscle cell
Endomysium
separates muscle fibers
structural role; but also contains specialized laminins to repair neuromuscular junction
signaling molecules
Perimysium
wraps around the bundles of muscle fibers
contains arteriols and nerve bundles
Epimysium
covers the muscle; thick connective tissue for protection
Embryonic Development of myoblasts
myoblast fusion of muscle fibers
fushion to form long cells.
myoblasts are most active during development but exist as satellite cells during adult life
Sarcomere
repeating units in striated muscle; basic unit of contraction.
Relaxed state is 2.5 um; but continually change length depending on level of contraction.
Bring Z discs together
Thin Filament
made of actin; specifically F actin
1 um in length
double stranded and helical
bound to two regulatory proteins troposmyosin and troponin
Tropomyosin
rod shaped regulatory protein that binds to 6-7 actin
covers actin binding site to myosin when relaxed.
When calcium binds to troponin, induces change in tropomysin and exposes actin and mysoin binding sites.
Troponin
heterotrimer that binds to one end of tropomyosin
Ca sensitive
Ca causes binding to troponin and undergoes conformational change to induce change in tropomysoin and facilitate actin binding to myosin.
Thick filaments
myosin (1 pair heavy chain and 2 pairs light chains)
situated in a staggered foramtion
1.6 um long and contains 300-400 myosins
Region of ATPase activity
When does the power stroke occur?
moment actin binds to mysoin.
at resting state, Myosin is locked in spring form.
ATP binds to release myosin from actin.
ATP hydrolysis puts myosin in high energy state.
how big is a power stroke?
8 nm
Different of myosin turn over in fast vs slow twitch muscle
Fast: 20 times per second
slow: 5 times per second
Cardiac muscle contraction
occurs in process similar to skeletal muscle
Smooth Muscle Contraction
contains no troponin
Calcium binds to calmodulin, which together activate CaMKinase. This phosphorylates light chain of mysoin.
Phosphorylated myosin binds to actin to generate force
relaxation occurs by dephosphorylation.
slower process than in smooth muscle
Dystrophin
large filamentous protein associated with actin near PM.
links cytoskeleton with ECM
Titin
maintains highly ordered sarcomeres
links myosin Z disk
Nebulin
associates with actin and keeps thin filaments organized
passive tension in muscle
Alpha-Actinin
cross links actin filaments
Tropomodulin
caps length of actin filament - end
CapZ
caps to + end of actin
Hypertrophic Cardiomyophathy
50% of sudden cardiac death
left ventricular thickening
Mutation in myosin heavy chain that binds to actin and ATP
due to missense mutations in many different genes.
Phenotype of Hypertrophic cardiomyopathy
Cardiomyocyote hypertrophy
Myocyte disarray –> compromises contraction
Fibrosis –> arrhythmia
Displastic intracmyocardial arterioles –> ischemia
Symptoms of hypertrophic cardiomyopathy
usually asymptomatic
but dyspnea, angina, syncope, cardiac death (enriched in athletes)
Clinical Presentation of Hypertrophic cardiomyopathy
Carciac murmer, cardiac pump failure (dyspnea, angina) arrhythmia (syncope, sudden death), family screening
Rate of diffusion compared to distance
rate decreases by distance squared
Paravlbumin
binds and releases Ca and diffuses father than Ca
mechanism to increase evenness of contraction
Myoglobin
binds to O2 and stores O2
What replenishes ATP during metabolic demand in muscles
Creatinine and phosphocreatine
Transverse Tubules
deep invagination of the sarcolemma, which is the plasma membrane of skeletal muscle and cardiac muscle cells
allows for propagation of signal along length and depth at the same time.
Sarcoplasmic Reticulum
specialized type of smooth ER that regulates the calcium ion concentration in the cytoplasm of striated muscle cells
puts calcium release within 1 um of all muscle cells.
uniform calcium release
Excitation Contraction Coupling in Skeletal Muscle
Action potential in motor nerve causes ACh release to activate ACh channel to open and depolarization. Depolarization popogates and occurs in T tubules.
Protein links at T-tubule/SR junction *(triad) are altered to allow Ca release from RyR channels.
Ca binds to troponin and alters Tropomysoin conformation and allows actin to bind.
As long as Ca and ATP are present, contraction continues.
When does relaxation occurs in skeletal muscle
Ca ATPases pumps Ca back into SR and tropomyosin blocks myosin actin binding site.
DHPR
Dihyropyridine receptor
voltage gated channel in T tubule
RyR
Ca release channel in SR
in Skeletal muscle: DHPR conformational change due to depolarization induces a change in RyR to open and release Ca.
Malignant Hyperthermia
mutation in RyR to cause prolonged Calcium release.
Catastrophic rise in body temperature when exposed to volatile anesthetics because of heat generated to pump Ca back into SR
Dominant disorder
Environmental disorder: okay unless exposed to the anesthetic
Volatile Anesthetics in malignant hyperthermia
halothane
succinylcholine
Phenotype of malignant hyperthermia
hypermetabolism, skeletal muscle damage, hyperthermia
Specific clinical signs of maligant hyperthermia
muscle rigidity (masseter spasm), increased CO2 production, rhabodomyolysis (muscle break down) hyperthermia
nonspecific signs of malignant hyperthermia
tachycardia, tachypnea, acidosis, hyperkalemia
What is given to malignant hyperthermia patients
Dantroelene 2.5 mg/kg to close RyR channel
Muscular Dysgenesis
lack of DHPR in skeletal muscle
Myostatin deficient
mutation that lacks control of skeletal muscle growth. Causes huge muscles
possible treatment for Duchenne muscular dystrophy
Muscular Dystrophy - Duchenne
cardiac myopathy is most common cause of death
high creatinine levels 1000s
mutation in dystrophin
Rigor Conformation
myosin is stuck to Actin because not enough ATP is represent for release
Cardiac E-C Coupling
same as skeletal, but Ca release is required from DHPR to bind to Ryr to trigger Ca release
E-C coupling in smooth
so thin that Ca easily diffuses throughout cell during entry
Motor units
muscle fibers innervated by a single motor neuron
vary in size depending on movement required.
Muscle fiber types
due to isoenzyme variation, myosin variation, proportion of mitochondira, oxidative enzymes, resistance to fatigue, speed of contraction
Slow Muscle fibers
maintained contraction
Red in color due to myoglobin content
Fast muscle fibers
high glycolytic content
rapid bursts of activity
Intermediate fibers
both glycolytic and oxidative enzymes
Gradiation of Tension
Increase frequency of AP
Recruitment of motor units
(smooth and cardiac depend on NT and hormone-like molecules)
Satellite cells
stems cells that are source of new myoblasts to repair injured muscle.
responsible to fibroblast growth factor, insulin GF, hepatocyte GF, NFKB, NO, myostatin
LIF tirggers proliferation
IL6 is secreted by exercise and triggers satellite cells.
Cardiac and Smooth muscle repair
fibroblasts generate scar tissue in heart
smooth cells dedifferentiate and enter mitosis to regenerate new muscle cells
changes to muscle with exercise
increases cross section
increase myosin and actin, but cells to not replicate.
NO real change in fast vs slow twitch, thus athletes are born not made.
Fatigue in muscles
(1) decreased propagation of the action potential into the t tubule
(2) decreased release of Ca+2 from the SR,
3) reduced effect of Ca+2 on the myofilament interaction
(4) elevated hydrogen and phosphate reduced force generation by the myofilaments
