Unit 4 Flashcards
1
Q
What is the (usual) source of energy in the cell?
A
ATP
2
Q
What are the principal sources of ATP in the cell?
A
Fatty acids and glucose
- glucose degridation occurs in cytosol
- terminal stages are called oxidative phosphorylation
3
Q
How were mitochondria believed to be incorporated in the cell?
A
via endocytosis (endosymbiotic hypothesis). Inner membrane is bacterial, outer is eukaryotic
4
Q
Describe mitochondrial membranes
A
- outer membrane is semi-permeable
- inner is much less permeable, contains most of the machinery for oxidative phosphorylation
- inner membrane SA is increased by cristae
- central space of mitochondria is the matrix
5
Q
How are proteins brought into the Mitochondria?
A
-majority are encoded in the nucleus
-synthesized in cytosol, imported via Translocate of Outer membrane (TOM) and translocate of inner membrane (TIM)
-TOM is passive, TIM is ATP-dependent
(TOM is TIM’s passive sub)
6
Q
describe fusion and fission
A
- fusion: plays key role in repairing damaged mitochondria. required for mitophagy.
- both depend on cellular GTPases: Mfn and OPA1 for Fusion, and Fis1 and Drp for Fission
7
Q
where is most of the free energy from oxidation contained?
A
NADH
- during respiration in mitochondria, electrons are released from NADH and transferred to O2 to make H2O
- achieved by 4 major protein complexes embedded in inner membrane
8
Q
What generates the proton concentration gradient?
A
- during electron transfer process, protons are pumped into inner membrane, that transport creates the gradient
- this also generates electrical potential across the inner membrane
- energy from NADH is stored as electric potential and proton concentration gradient
9
Q
What doe ATP synthase do?
A
- made up of F1 and F0.
- F0 spans the inner membrane and forms proton channel
- F1 is bound to F0 and is the enzyme that makes ATP
- 3 protons are needed to make 1 AtP
- once made ATP is transported out via ATP-ADP antiport
10
Q
How does mitochondria regulate cell death?
A
- cell damage induces Bak/Bax-dependent permeabilization of outer membrane
- this triggers release of cytochrome c
- cytochrome c binds the apoptosome
- apoptosome initiates caspases, and initiates apoptosis
11
Q
What can cause cell death via mitochondria?
A
- ischemic injury resulting in MPTP-dependent permeabilization of inner/outer mitochondria membranes (cytochrome release then and elimination of proton gradient)
- no proton gradient, no ATP
- absence of gradient, ATP synthase is converted to ATPase to use up ATP
- this causes necrosis and death
12
Q
Discuss some mitochondrial quality control
A
- damaged mitochondria produces no ATPand can generate excessive amounts of reactive oxygen (ROS) which damages cells and causes senescence
- mitochondria must control this via mAAA, iAAA, and Lon
- these recognize and degrade misfolded proteins
- mitochondria can fuse with healthy mitochondria
- elimiated with mitophagy
- if can’t fix, apoptosis
13
Q
list some mitochondrial diseases
A
- fusion machinery issues=autosomal dominant optic atrophy (OPA1 gene)
- Charcot-Marie-Tooth neuropathy type 2A (Mfn2 gene)
- hereditary spastic paraplegia (mAAA mutation)
14
Q
epithelia
A
- tissues that line body surfaces, cavities, surfaces of tubes/ducts/spaces in organs.
- adherent to one another
- polarized (asymmetric)
- avascular-nutrients must diffuse through
- highly diverse
15
Q
apical surface
A
- free outer epithelial surface
- exposed to fluids/environment
16
Q
basal/basolateral surface
A
-connected to underlying connective tissue
17
Q
basal lamina
A
- sheet of extracellular material lines, attached to basal surface and underlying connective tissue
- different basal lamina surround each tissue type
18
Q
functions of epithelia
A
- barrier
- absorption and transport
- secretion
- movement
- biochemical modification
- communication
- reception
19
Q
endothelium
A
tissue faces blood and lymph
20
Q
mesothelium
A
sheets of cells that line the enclosed internal spaces of body cavity
21
Q
mucosa
A
moist linings of the internal passageways. surface layer is an epithelium.
22
Q
epithelial to mesenchymal transition
A
epithelia disassemble and move into the mesenchymal tissues. there they may migrate to other locations to form new epithelia.
23
Q
layers/relationships of tissue systems (GI, reproductive, etc.)
A
1-outer epithelium
2-CT underneath (lamina propria)
-these both typically contain lots of immune system cells and small blood vessels
-deeper layers of CT are continuous w/lamina propr., but have diff properties and house other tissues (submucosa)
24
Q
skin layers
A
1-epithelium=epidermis
2-underlying CT=dermis
deeper=hypodermis
25
simple epithelia
cells arranged in single layer/sheet
26
stratified epithelia
more than 1 layer of cells where where outer layers don't directly contact basal lamina
27
pseudostratified epithelia
not all reach free surface but all rest on basil lamina
28
squamous cells
flattened cells
29
cuboidal
cube shaped cells
30
columnar
taller than they are wide cells
31
how are stratified epithelia named?
according to their outermost layer.
32
tight junctions
- highly selective barrier that limits/prevents diffusion of substances between epithelial cells
- limit/control diffusion of proteins through plasma membrane bilayer
- key core proteins are occluding and claudins
33
adherence junction
- promote attachment, polarity, morphological organization, stem cell behavior
- contain specific cadherins that link to actin filaments/other signaling proteins in cytoplasm
34
cadherins
transmembrane proteins w/ extracellular domains that interact with each other, and cytoplasmic tails that bind adapters/actin filaments
35
desomosomes
- promote mechanical strength, structural organization
- resist shearing forces
- include cadherins that link to intermediate filaments and other adapter proteins
36
gap junctions
-promote rapid communication btw. epithelial cells through diffusion ions/small molecules
37
plasma membrane: apical domain
- contains distinct membrane proteins and distinct phospholipid content compared to basal domain
- transporter enzymes, ion channels, receptors endo/exocytosis, signaling receptors/effectors, proteins that mediate cell-cell lamina attachments
38
plasma membrane: basal domain
- basal-lateral domain
| - protein and lipid content is similar on basal and lateral sides
39
transcytosis
endocytosis of substances form 1 membrane region, followed by trans cellular transport of vesicles and exocytosis form another membrane region
40
microvilli
- cell surface extensions that contain actin bundles connected to cytoskeletal elements in cell interior.
- increase SA to increase rate/efficiency of membrane transport/secretion
- sterocilia: found in epidemic an sensory cells in ear, sound functions
41
cilia
-microtubule containing extensions
1-primary cilia: single (1 cell) non motile microtubule based extension found on many diff layers. organize/promote signal transduction systems that control cell division, fate, function
2-motile cilia: related microtubule extension that move, found on specific cell types. wave to move materials.
3-sensory cilia: not motile, appear to function in sensory reception
42
basolateral surface modifications
- in/out folds of basolateral membrane in epithelial cells
| - increase SA, seen in cells that transport heavily from basolateral surface
43
basal lamina
- thin sheet of extracellular material that underlies basal lamina of each epithelial tissue
- surround many other cell/tissue types.
- formed by network forming collagen, forming thin sheets of fibers that are interwoven with extracellular glycoproteins
- function: mediate attachment to underlying tissue, highways for migration of cells, establish/maintain polarity, barrier to microbes, control gene expression cells, act as tissue scaffolding
44
how doe epithelial cells connect to basil laminae?
- hemidesmosomes and focal adhesions
| - these connections are formed by integrins
45
epithelial stem cells
- competent for division
- self renew (regenerate mother cell)
- produce differentiated cell types specific to each epithelia
- produce transit amplifying cells (daughters that proliferate themselves quickly, that then produce differentiated cells)
46
typical cell signaling pathway
- extracellular ligand secreted
- receptor in receiving cell binds, then is activated/inactivated by ligand
- downstream effector proteins
- modulator proteins promote/suppress
- can be local or far away
47
exocrine glands
secrete materials onto epithelial lined surfaces or the outside world
-secrete onto apical side
-multicellular
2 main components:
1-secretory units (produce/secrete bulk of secretion)
2-ducts (tubular structures that emanate out, modify secretion content)
48
endocrine glands
secrete substances into bloodstream
- no ducts, secrete into bloodstream
- produce specific hormones over long distances
- hormone molecules must cross basal, basil lamina, and then go through basal and endothelial layer of capillary to reach bloodstream, so most endocrine cells secrete from basolateral membrane
49
adeocarcinomas
cancers derived from glandular tissue
50
carcinomas
epithelial origin cancers
| result from defects in regulatory pathways
51
Cystic fibrosis basics
-autosomal recessive
-multisystem syndrome, affects 1/3000 caucasians; 1/9000 hispanics.
-defect in ATP binding cassette transporter gene on chromosome 7 encoding for CFTR protein
(most common mutation is F508del)
-lung involvement is main cause of morbidity/mortality
52
typical clinical features of CF
- sinus: chronic sinus infections, nasal pollyps
- lung: recurrent respiratory infections
- pancreas: exocrine pancreatic insufficiency
53
How is CF identified?
- mostly in newborn screen
- at birth with meconium ileus
- failure to thrive
54
How do you treat CF?
- nutrition
- targeted lung therapies
- antibiotic therapies
- anti inflammatory treatments
- CTFR modulators
55
basal bodies
- core anchors from which cilia are formed
- microtubule rich cylinder from 9 triplet microtubules
- ABC tubules
- polarized structure
56
axoneme
- structural skeleton of cilium
- formed from doublet microtubules
- AB tubules
- plus end is at ciliary tip
- provide tracks of movement w/in cilia
57
transition zone
- links basal body to axoneme and ciliary membrane
| - limits the diffusion of membrane and soluble protons into/out of the cilium
58
ciliary membrane
- continuous with cellular plasma membrane
| - compartmentalized so it is distinct
59
intraflagellar transport (IFT)
- signaling components transport along the axoneme by IFT
- bidirectional w/ kinesin motors
- IFT-B protein complex directs moments to ciliary tip, with retrograde movement directed by cytoplasmic dynein 2 motor with IFT-A protein complex
60
ciliary assembly
1-centrioles/basal bodies are assembled
| 2- formation of cilium
61
centrioles and their connection to cilia
- basal bodies are derived from centrioles, so centrioles change btw function at centrosomes to organize cellular carry of microtubules during interphase/mitosis
- centriole duplication occurs during G1-S, tightly regulated to limit to a 1x replication during the cell cycle
- older centriole is mother basil body in subsequent G1
62
ciliogenesis
- occurs during G1
- assembling from the mother centriole (distal end of basal body is capped by ciliary vesicle)
- microtubule doublets assemble int ciliary vesicle
63
motile cilia
- required for movement of fluid in respiratory, neural, reproductive tracts
- produced by axonemal dyne dependent sliding motion
- 9+2 arrangment
64
non motile/sensory/primary cilia
- possess 9+0 arrangement
- lack axonemal dyne arms
- signaling functions
65
what can cilia sense?
- physical stimuli, light, chemical stimuli
| - these can all produce downstream effects
66
ciliary node
- establishes R-L asymmetry in the body
- node=invagination of cells formed during gastrulation on mid plate
- nodal cilia=9+0 organization and beat in rotary fashion
- angled to form leftward flow
67
extracellular matrix (ECM)
- structural fibers, glycoproteins, and polysaccharides secreted by a relatively small number of cell
- common origin from precursors
- near body surface forms nearly continuous compartment of relatively loose and easily distinct layers of connective tissue
68
deep fascia
- tougher region of dense, connective tissue including epimysium of muscles
- organized into specific functional units (ligaments, joints, tendons, capsules, coverings)
69
functions of connective tissues
1-provide mechanical strength/support
2-conduct/control exchange of nutrients, metabolites, signaling ligands
3-directly control the behavior and functions of cell that contact the ECM
70
regulatory functions of CT
- control epithelial polarization, shape
- guidance, regulation of cell migration through matrix
- control of cell proliferation, differentiation, metabolism
- defense against infectious agents
- control tissue formation, organization, modification
- control of inflammation
71
resident cells of CT
produce and secrete components of ECM, many can proliferate to produce new connective tissue
72
mesenchymal cells
precursors to all the connective tissue family members. primarily function embryogenesis
73
fibroblasts
pre-eminent cells of most connective tissues in the body
74
myofibroblasts
derivatives of fibroblasts are capable of smooth muscle-like function, found in connective tissues that require contractile function. Generated at site of wounds
75
adipocytes
derivatives of fibroblasts and or primitive mesenchymal cells. founding adults-store fat as energy for other cell types
76
osteoblasts and osteocytes
make bone
77
osteoclasts
break down bone
78
chondrocytes
make cartilage
79
smooth muscle cells
make some of the extracellular matrix components which they are embedded in.
80
immigrant blood-derived cells
white blood cells that are produced from blood cell precursors in the bone marrow and migrate from blood into connective tissues. Part of the immune system
81
lymphocytes
central to acquired immunity to foreign organisms/viruses/materials
82
macrophages
large "engulfing" cells that phagocytose: cells, ECM, other non-cellular material. critical regulatory cells that secrete and respond to extracellular signals
83
physiological functions of macrophages
engulf invading microorganisms
promote blood vessel formation (angiogenesis)
remodel damaged tissue
remodel normal developing tissue and organs as part of morphogenesis
84
neutrophis and eosinophils
important for defense against microorganism
85
mast cells
secretory cells that release various responses to immune signals (vasodilators)
86
osteoclasts
phagocytic cells that appear to be derived from blood monocytes, similar to macrophages. function in bone resorption
87
fibroblasts
central CT cell type that make the components of he extracellular matrix of most connective tissues.
- secretory machines (produce fibrous proteins, proteoglycans, other components of ECM), capable of dividing to make new fibroblasts, more made in response to injury
- made up of a collection of diverse, closely related cell types
- developmentally flexible (transform into other connective tissues cell types)
88
ECM components
- structural fibers which provide mechanical strength and resiliency
- hydrated gelatinous material (ground substance) where structural fibers are embedded
- numerous extracelluar macromolecules
89
collagen
- most abundant fiber in ECM.
- made up of large family of related proteins
- similar primary sequence
- 3 intertwined polypeptide chains that form rope-like triple helix (alpha chain)
- 25 diff alpha chains, different combinations leads to formation multimeric collagens of 17 types
90
fibrilar collagen
- some collagen molecules assemble into large bundles-->fibrils
- aligned head to tail, generate length, stacked to generate fibril thickness
- strength to resist tensile strength in tissues
91
fibril-associated collagen
-decorate the surface of collagen fibrils, thought to link fibrils to each other tissue components and each other
92
network forming collagen
- form very thin fibers and assemble into interlaced networks that from porous sheets
- found in basil lamina, also as anchoring fibers attach basal lamina and cells to ECM
93
loose connective tissue
- thin collagen fibrils that are relatively sparse, arranged in latices
- cell densities and ground substance components are high in loose connective tissue
94
dense connective tissue
- thick collagen fibrils that are very abundant relative to ground substance, low number of cells
- collagen bundles are arranged in irregular orientations or in parallel-organized sheets
95
how is collagen sythesized?
- intracellularly
| - secreted and modified extracellularly
96
intracellular synthesis of collagen
- collagen peptides are synthesized on ER and translocated
- post translationally modified
- assembled in a triple helix
97
extracellular synthesis of collagen
- n and c terminuses are cleaved by proteases
- n-terminal fragments (n-telo peptiedes), clinically important since presence in urine used to diagnose connective tissue and bone disease
- formation of bundles and end-to-end polymers of collagen fibrils
- enzymes catalyze chemical cross links
98
elastic fibers
-elastin and fibrillin: assemble into stretchable and resilient fibers and sheets
99
elastin
filamentous protein in random coil conformation, can be stretched upon exertion of force
extracellularly they form filaments and sheets were molecules are highly cross linked
100
fibrilin
elastin is interwoven with fibril, helps organize the elastin elements in the fiber and organize the elastic fibers with other components of extracellular matrix.
101
ground substance
- made of proteoglycans (GAGs)
- other secreted proteins and glycoproteins (proteases that process collagen, etc.)
- inorganic and small organic solutes
- water
102
proteoglycans
- highly negatively charged
- rigid extended structure causes them to readily form gels
- some proteoglycans can bind to and inactivate or activate other proteins
103
what happens when wound occurs?
- inflammation and blood clotting (increase water permeability of capillaries, increase cell permeability, attract migration blood cells in to CT, white cells to wound, stimulate fibroblast proliferation)
- new tissue forms (fibroblasts stimulated to divide)
- tissue remodeling
104
bone functions
1-protect critical organs
2-mechanical support for locomotion
3-calcium and phosphate homeostasis
4-house, protect, regulate stem cell precursors of blood cells
105
differences between bone and cartilage as tissues?
- bone is highly dynamic: vascular, constantly turned over and remodeled
- cartilage is much less dynamic: avascular, grows in fetus then slows, is template for bone
106
what are the two main functions of cartilage?
- provide resilient but pliable support structure
| - direct the formation and growth of bone
107
chondrocytes
- make cartilage matrix and tissue
- arise primitive mesenchymal cells during fetal development
- once cartilage formed, can arise from external layer of connective tissue (perichondrium)
- undifferentiated mesenchymal cells, fibroblasts generate during growth
- secrete an surround themselves with matrix, become isolated from other cells, coming to reside in a compartment (lacunae)
- secrete special extracellular matrix
108
hyaline cartilage
- collagen that forms thin fibrils arranged in irregular 3D pattern
- rich in proteoglycans and free glycosaminoglycan hyaluronic acid (promotes hydration/flexibility)
109
structural properties of hyaline cartilage
- allows metabolites to diffuse through tissue
- promotes resiliency to compression forces during joint movement
- allows growth of chondrocytes and matrix from within matrix
- during growth, can calcify and attract cells that initiate bone formation
110
elastic cartilage
-contains thin collagen fibrils and proteoglycans, distinguished by abundant elastic fibers and interconnecting sheets
111
fibrocartilage
-contains large bundles of regularly arranged collagen that is similar to dense regular connective tissue, designed to resist compression and sheer forces
112
is cartilage avascular?
Fuck yes. he said this about 8,000 times.
| Also know how it grows
113
diaphysis
central shaft
114
epiphysis
expanded ends
115
spongy bone
has thin anastomosing spicules called trabeculae
116
what does bone marrow consist of?
- hematopoietic tissue or adipose
| - results in 2 different surfaces: periosteum (dense connective tissue) and endosteum (internal soft tissue with many)
117
osteoprogenitor cells
stem cells capable of cell division to generate osteoblasts and osteocytes. present in both personal and endosteal surfaces
118
osteoblasts
- inner layers of both perosteal/endosteal surfaces where bone growth is occurring
- secrete initial un-mineralized extracellular matrix of bone (osteoid)
119
osteocytes
- directly derived from osteoblasts
- forma as become surrounded by bone matrix in lacuna
- do not divide
- extend long processes through tiny channels (canalliculi)
- retain limited ability to modify matrix
120
osteoclasts
- not related by lineage, derived from monocytes in blood
| - reliable and are related to macrophages
121
bone matrix
- most extracellular matrix is calcified/packed with dense parallel collagen fibers
- contains negatively charged particles
- mineralized or calcified
122
bone is vascular and innervated
- threading through matrix of bone tissue
- relatively short distances of diffusion
- long bones, channels traverse the long taxi through compact bone called Haversian canals
- bone lamellae tend to surround a canal in a ring called osteon
123
intramembranous ossification
- absence of pre-made cartilage tissue
- groups of mesenchymal cells come together (condensation)
- transformation into osteoprogenitors, differentiate into osteoblasts
- secrete osteoid
- bone islands join
- intially bone matrix is trabecullae
124
endochondral ossification
- within previously made cartilage tissue
- generates various structures of skeleton that will become bone
- some cells in perichondrium converted to osteoprogenitors
125
appositional growth
growth from within
-in the perichondrium at cartilage surface, mesenchyme/fibroblasts proliferate and differentiate into more chondrocytes which secrete more hyaline matrix
126
interstitial growth
- growth from within
| - chondrocytes embedded in matrix continue to proliferate w/in their lacunae and secrete ECM, internal growth
127
replacement of cartilage by bone
- collar of bone forms
- mesenchyme develop developing into osteoprogenitors, become osteoblasts
- periosteum
- chondrocytes enlarge, become calcified
- osteoclasts are recruited, degrade the calcified cartilage matrix
- blood vessels grow into degraded region bringing connective tissue carrying more osteoprogenitors
128
growth of long bones
- long bones grow in length and diameter
| - cartilage is critical point for length growth
129
where does bone resorbtion occur?
on the endosteal surface
130
how does calcification of the matrix occur?
- osteoblasts initiate mineralization of osteoid by secreting matrix vesicles
- pinch off matrix vesicles, filled with PO4 and Ca2+, these act as nucleation sites away from the bone
131
how is bone and cartilage regulation mediated?
- short range signals (local bone environment): BMPs (proteins secreted by cells, bind surface receptors, trigger intracellular protein phosphorylation, alter gene expression
- long range signals (endocrine glands)
- mechanical stress (bone remodeling patterns)
- neuronal stimulation (CNS can regulate bone metabolism)
132
control of calcium homeostasis
- calcium mobilization from bone
- tight regulation from endocrine hormones
- Parathyroid hormone (bone resorption)
- calcitonin (stimulates calcium uptake into bone)
133
how much of an increase is there in the number of vessels from the aorta to the blood vessels?
2-3 billion fold
| 500 fold increase in cross sectional diameter
134
how is capillary design different from other vessels?
capillaries and post capillaries are designed for exchange, other vessels are designed for mass circulation
135
where is flow the slowest?
capillaries and venuoles
136
tunica intima
inner layer of vessel, contains layer of endothelial cell in intimate contact with the blood in addition to a layer of elastic, loose collagenous tissues containing intimal cells
-the underlying layer of collagen/elastin rich fibers contains fibroblasts and myointimal cells (similar structural features to smooth muscle cells)
137
tunica medi
layer in the middle of a vessel, comprised of multiple layers of elastic laminae, smooth muscle cells, collagen
138
tunica adventitia
comprised of collagenous tissue (collagen and elastin). In larger vessels it contains vasa vasorum
139
vasa vasorum
supply oxygen and nutrients to the adventitia and outer part of the media, since it cannot diffuse to these regions from inside the vessel
140
arteries
thick walled, same wall thickness as the lumen itself. largest arteries have thick media with multiple elastic layers, but the layers decrease as you go to arterioles.
-smooth muscle is in the media from aorta to arterioles which permits control of blood flow to capillary beds
141
why do arteries have an elastic layer?
crucial for permitting expansion of vessels after systolic contraction of the heart, dampening systolic blood pressure.
-aorta and larger arteries branching from it are the elastic layer
142
muscular artery layers
multiple elastic layers in elastic arteries are restricted to 2 layers:
1-inner elastic lamina (btw. intima and media)
2-outer elastic lamina (boundary btw. media and adventitia)
143
smaller muscular arteries
- lose outer elastic lamina
- keep inner elastic lamina
- intima is made of endothelial layer and thin layer of collagenous material
- relatively large layer of smooth muscle in the media (can contract vessel diameter)
- adventitia is same width as the media and merges with surrounding connective tissue
144
arterioles
- contain inner lining endothelial cells on thin, basement membrane
- surrounded 1-2 layers smooth m. and outer collagenous tissue which blends in with surrounding connective tissue
- gatekeepers to local capillary beds, can restrict blood flow through them
145
metaterioles and arteriole venule shunts
- connect larger arterioles and venules
| - vasoconstriction/dilation directs blood flow through/bypasses capillary beds
146
capillaries
- smallest vessels (5-15 microns)
- 1-2 endothelial cells surrounding the lumen
- no muscular layer, instead surrounded by pericytes (unspecialized cells that give rise to smooth m. cells during vessel growth and wound healing-may be contractile)
- surrounded by collagenous fibrils, connect capillary to adjacent connective tissue
147
where does most of the molecular traffic btw. vascular system and tissues?
- capillary endothelium, much of the exchange by diffusion
| - 2 main capillaries are recognized: continuous and fenestrated
148
fenestrated capillaries
pores or fenestrations in the endothelial cells, allow for bulk flow of plasma past endothelial boundary
149
continuous capillaries
endothelial cells form uninterrupted lining, although transfer can occur via pinocytotic vesicles
150
sinusoidal capillaries
endothelial cells are separated by wide pores (discontinuous) large enough to permit RBC to pass (spleen)
151
post capillary venules
- capillaries empty into these vessels
- similar structurally, just larger
- surrounding pericytes
- leukocyts primarily diapedese through vessel walls
- responsive to vasoregulatory substances (serotonin, histamine), regions are more sensitive to controlled permeability
- larger ones get 1-2 layers of smooth muscle in media (muscular venules) within thin layers of connective adventitia
152
veins
- thin walled
- collapsed structures for viewing
- wall thickness increases with diameter
153
small veins
- intimal layer endothelial cells and no inner elastic lamina
- media is 2-4 layers smooth muscle
- adventitia is collagenous
154
medium sized veins
- similar endothelia lining and muscle layer to small veins
| - increasing thickening of tunica adventitia (thickest layer)
155
large veins
- thin intimal of endothelial cells
- media of interlayered smooth m. and collagen (5-7 layers)
- small amounts of elastin
- tunica is thick, and in larger veins has vasa vasorum
156
how is blood circulated in veins?
- via hydrostatic pressure
- aided by contraction of smooth muscle and compression of skeletal muscles
- blood is prevented from back flow via one way flap valves
157
pulmonary arteries
- low pressure function (15-25 mmHg)
| - structure is different from systemic arteries
158
lymphatic flow and structure
- one way from tissues to empty into blood on R and L side near IJV and Subclavian Veins
- begin as small spaces in connective spaces
- become larger spaces lined with thin squamous epithelium
- lymph is light pink
159
anastomoses
-connections btw. arteries and veins that permit collateral circulation to occur within tissues
160
end arteries
-supply a section of tissue that cannot have an alternate arterial supply (found in lung and kidney)
161
portal systems
- portal systems begin in capillary beds and end in capillary bed
- found in hypothalamic-anterior pituitary and hepatic portal system
162
pampiniform plexus
- countercurrent arrangement btw. artery and venous network
| - spermatic cord for optimal heat exchange
163
three classes of muscle?
cardiac, skeletal, smooth
164
muscle histology
- long, cylindrical cells (muscle fibers/myofibers
- 50-100 um wide, cm long
- 100's of nuclei on the periphery
- repeating myofilaments for striped appearance
165
types of skeletal muscle
fast (2 types) and slow twitch
- fast has higher myosin turnover (20xs per sec)
- slow muscle turns over slower (5xs per sec)
166
cardiac muscle fibers
- single nucleus
- smaller diameter
- shorter than skeletal
- intercalated disc (prevents adjacent cells from pulling apart, contains gap juct.)
167
smooth muscle
- single nucleus
- thinnest diameter
- spindle shaped with nucleus near the center
- not striated, but use the same proteins to generate force as skeletal and cardiac
168
sarcomere
- striated muscles have these repeating units
- units of contraction from 1 Z line to the next Z line
- made of thick and thin filaments
169
myofibrils
- bundle of contractile filaments
- covered with own sarcoplasmic reticulum
- 2 primary filaments (thin-actin, thick-myosin)
- 2 regulatory proteins: tropomyosin, troponin
170
thin filaments
- F actin makes thin filaments
- 1 um long
- DS and helical (2 strings of twisted pearls)
- troponin and tropomyosin are bound to this
- tropomyosin binds 6-7 actin molecules of 1 strand
- troponin binds end of tropomyosin
171
2 types of actin
-G actin (globular) or F actin (filamentous)
172
thick filaments
- made of myosin (6 proteins that are made of 3 pairs: 1 heavy, 2 light chains)
- heavy chains form alpha helical region w/globular head, they wrap around each other
- light chain location unknown
- rod region of myosin associates with other myosin
- thick filaments=1.6 um long
173
cross bridge interactions
- binding of myosin is prevented in relaxed state (binding site covered by tropomyosin)
- Ca2+ binds troponin, changes confirmation, binding site exposed
- myosin head binds actin, energy released on binding, myosin head rotates, sarcomere shortens (8nm)
- head is stuck on Actin until ATP binds, allows it to dissociate
- summation of linear shortening, and many cycles of shortening back to back cause contraction
174
smooth muscle contraction
- no troponin, but calcium is still regulatory molecule
- Ca2+ binds calmodulin, and the Ca-calmodulin complex binds CaM kinase
- this activates so light chain of myosin is phosphorylated
- then can bind actin and generate force!
- much slower than skeletal muscle
- Ca2+ removal done by Ca pumps and Na-Ca exchanger
- inactivates kinase
- phosphokinase dephosphorylates myosin
- can remain bound in contracted state without using ATP
175
dystrophin
- protein where mutation in the gene results in DMD
- large, filamentous protein associated with actin and membrane surface
- part of a complex protein that spans the plasma membrane and binds ECM, links cytoskeleton w/ ECM
176
titin, nebulin, and alpha actinin do what?
-maintain the highly ordered structure of sarcomeres
177
titin
- large protein that links myosin thick filaments to Z line
- part is bound to myosin (inflexible)
- keeps filaments centered in sarcomere
178
nebulin
-large protein associated with actin, important for keeping thin filaments organized
179
alpha actinin
crosslinks actin filaments at the Z line
180
familial hypertrophic cardiomyopathy (FHC)
- 1/2 of cases sudden death in young athletes
- thickened left ventricle
- mutations in heavy chain (head region), sometimes troponin
- single aa mutation in regulatory region can produce muscle disease
181
events of a single contraction
- normal, relaxed muscle Ca2+ is low
- membrane events cause increase in Ca2+
- action potential causes release of ACh, diffuses across synaptic cleft to an ion channel that opens and causes depolarization, Na channels are opened and an action potential occurs
- action potential is very fast compared to contraction
182
how do skeletal muscles contract uniformly and rapidly?
- striated muscle has carriers for Ca2+, O2, ATP and storage mechanisms to overcome slowness/barriers of diffusion over large distances
- Parvalbum-Ca2+ bp, binds and releases Ca to diffuse quickly
- myoglobin binds O2 and stores it
- creatinine an phosphcreatinine replenish ATP in high demand
183
what 3 molecules are critical for signaling and energy?
-Ca2+, O2, ATP
184
what 2 structures have evolved for speed and storage of materials for contraction?
transverse tubule system and sarcoplasmic reticulum
| -these 2 allow electrical signal to take place everywhere in cell in milliseconds
185
transverse tubule system
- membrane structure allowing action potential to propagate through cross section of cell
- goes rapidly along cell length, and into the depths of the cell at regular intervals
186
sarcoplasmic reticulum
- each myofibril has "stocking" of SR
- around the bundle, Ca2+ is stored
- shortens the distance so diffusion can occur in microseconds
187
Where is Ca2+ stored in the cell?
- intracellular storage compartments, often in the ER (smooth)
- this is similar to the muscle's SR
188
how is Ca2+ released from the SR?
- action potentials are transmitted via the t-tubule membrane
- (Huxley and Taylor experiment)
- depolarization in t-tubule doesn't go directly to SR since no electrical continuity btw. SR and t-system
189
what are the structural components in E-C coupling?
- myofiliments bundle into myofibrils
- myofibril is wrapped into an SR
- end of SR contacts T-tubule (terminal cisterna-contains calsequestirin)
- at apposition, there is an electron dense region called the triad
190
what does calsequestrin do?
-each molecule binds ~50 Ca2+
191
what are the complexes that connect the t-tubule and SR?
- DHPR (dihydropyridine receptor): complex of several membrane proteins in T-tubule membrane. Subunit contains Ca-channel (voltage gated)
- RyR (ryanodine receptor): in the SR membrane, Ca-release channel
192
mutations in t-tublue/SR can cause what diseases?
- abnormal Ca release channel=malignant hyperthermia
| - no DHP receptor=muscular dysgenesis (E-C coupling is interrupted, death is result)
193
list the sequence of events that occur during a single contraction
1-action potential motor nerve
2-ACh release
3-ACh binds receptor, opens, depolarization
4-action potential!
5-depolarization in t-tubules
6-protein links at t-tubules/SR junction (triad) are altered so Ca2+ releases from SR
7-tropoin bound by Ca2+, tropomyosin confirmation altered, myosin binding site exposed
8-cycle continues in presence of Ca2+ and ATP
9-relaxation (Ca2+ and ATP pumped back, tropomyosin blocks myosin binding site)
194
what is the difference between smooth and cardiac muscle for E-C coupling?
- Ca2+ entry is needed to trigger the release channel to let out Ca2+ from the SR (since this channel binds Ca)
- smooth muscle in comparison doesn't need t-systems or SR, since they are so thin Ca2+ can just diffuse right in
195
what is the relationship between length and tension for a muscle fiber?
- when the fiber is stretched so there is no overlap, no tension exists
- tension increases linearly as overlap increases
- when the actin filaments move where there are no more myosin head groups, tension is at a plateau
196
how many muscles does 1 motor neuron innervate?
-1 muscle and a subset of fibers in that muscle
197
how does the size of a motor unit relate to the type of work a muscle does?
- muscles doing fine work=small motor unit (a few fibers)
- large/gross movements=large motor unit (several hundred fibers)
- cardiac fibers are innervated but work without nervous innervation
198
what are the 3 groups of skeletal muscle?
slow, fast, intermediate
| -virtually all muscles are a mix of these
199
slow oxidative fibers
- postural or maintained contraction
| - red due to high myoglobin content
200
intermediate fibers
- fast with glycolitic and oxidative enzymes
| - fast twitch=rapid bursts of energy
201
how do skeletal muscles recover from damage from exercise?
- satellite cells (stem cells) are source of new myoblasts and they repair injured muscle
- they divide and fuse to form new muscle cells (if damage is too extensive)
- damaged muscle cells produce factors like LIF that trigger satellite cell proliferation
- more myofilaments are added during exercise, and satellite cells divide and fuse to support extra volume
202
satellite muscle cells
-responsive to large number of signaling molecules
(FGF, IGF, HGF, NF-kB, NO, myostatin)
-in DMD, cells are constantly weakened and damaged by no dystrophin, satellite cells must work to fuse and repair until they are depleted
203
how does repair occur in cardiac and smooth muscle?
- no satellite cells in cardiac muscle
- smooth muscle can repair itself, cells can dedifferentiate (enter mitosis, regenerate new muscle cell). this proliferation can result in tumors (leomyosarcoma)
204
what effect does exercise have on muscle?
-hypertrophy (new myofibrils added)
| conversely if you don't exercise you atrophy
205
muscle fatigue in exercise
-reduced performance in prolonged/intense activity
-decrease in force and speed
-fatigue affects:
1-propogation into t-tubule
2-release Ca2+ from SR
3-effect of Ca2+ on myofilament interaction
4-force generation
-most often due to metabolic changes: increase in inorganic phosphate, decrease in pH from 7-6.5. this reduces force
206
smooth muscle innervation
- done by sympathetic and parasympathetic neurons
- utilizes a bunch of CNS neurotransmitters and peptides
- NO=relaxation by binding cGMP
- some smooth muscles create action potential, from Ca2+ (not Na). EG: muscles in gut, uterus, bladder, arterial smooth muscle, trachea, gastric funds
207
Hypertrophic cardiomyopathy
-autosomal dominant
-heterogeneous
-incomplete penetrance
1/500 individuals
208
Hypertrophic Cardiomyopathy Cellular Consequences
- missense mutation
- incompletely understood (over-robust contraction?)
* cardiomyocyte and cardiac hypertrophy (organ hypertrophy)
* myocyte dissaray (function compromised)
* interstitial and replacement fibrosis (propensity to arrhythmia)
* dysplastic intramyocardial arterioles (ischemia)
209
HCM phenotype in Patients
- most are asymptomatic but some can have dyspnea, angina, syncope, sudden death
- clinically presents as: *cardiac murmur, cardiac pump failure, arrhythmia, sports/family screenings find it
- diagnose via EKG, echo, MRI, family history, genetic testing, chest-xray
210
if you see a healthy athlete with murmur and SCD what do you think?
HCM!!!!!!
211
myostatin and skeletal muscle growth
muscle growth:
-mature muscle cells can't divide, recruit myoblasts for length/girth
myostatin:
-normally made an secreted by muscles as negative feedback for muscle growth
-may be increased in AIDS patients (possible pathologic role?)
212
malignant hyperthermia
-dominant
-RyR1 mutations (~70%)
-caused from inhalation of *halothane or *succinylcholine
-1/5000 to 1/10000 anesthesia exposures, ~600 cases a year
phenotype:
-hypermetabolism, skeletal muscle damage, hyperthermia
-die if untreated
213
what 2 anesthesias cause malignant hyperthermia?
halothane, succinylcholine
214
What occurs in a malignant hyperthermia event?
- depolarization
- Ca2+ channel opens
- channel does not close
- muscles cannot stop contracting over and over, go until ATP exhausted
215
clinical signs of malignant hyperthermia
- muscle rigidity, particularly *masseter spasm
- increased CO2
- rhabodomyolysis
- hyperthermia
- halothane/caffeine test on muscle biopsy
216
if you see someone with masseter spasm and hyperthermia, what do you think?
MALIGNANT HYPERTHERMIA!
217
how do you manage malignant hyperthermia?
```
with DANTROLENE (2.5 mg/kg)
-stops spasms, targets RyR receptor and blocks the Ca2+ channel
```
218
duchenne muscular dystrophy
-x inked
-1/3500 males
-dystrophin mutations
-abnormal gait, toe walking
-gower's sign
-calf pseudohypertrophy
-high creatinine Kinase (1000s)
-mild intellectual disability
~age 11 wheelchair bound
~death in 20's (cardiopulmonary
*cardimyopathy 100% by 18 years
219
how prevalent is cardiomyopathy in DMD?
100% of all cases by adulthood
220
how do you treat DMD?
corticosteroids
| -prolong independent adulation (has side effects)
