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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
Q

simple epithelia

A

cells arranged in single layer/sheet

26
Q

stratified epithelia

A

more than 1 layer of cells where where outer layers don’t directly contact basal lamina

27
Q

pseudostratified epithelia

A

not all reach free surface but all rest on basil lamina

28
Q

squamous cells

A

flattened cells

29
Q

cuboidal

A

cube shaped cells

30
Q

columnar

A

taller than they are wide cells

31
Q

how are stratified epithelia named?

A

according to their outermost layer.

32
Q

tight junctions

A
  • 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
Q

adherence junction

A
  • promote attachment, polarity, morphological organization, stem cell behavior
  • contain specific cadherins that link to actin filaments/other signaling proteins in cytoplasm
34
Q

cadherins

A

transmembrane proteins w/ extracellular domains that interact with each other, and cytoplasmic tails that bind adapters/actin filaments

35
Q

desomosomes

A
  • promote mechanical strength, structural organization
  • resist shearing forces
  • include cadherins that link to intermediate filaments and other adapter proteins
36
Q

gap junctions

A

-promote rapid communication btw. epithelial cells through diffusion ions/small molecules

37
Q

plasma membrane: apical domain

A
  • 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
Q

plasma membrane: basal domain

A
  • basal-lateral domain

- protein and lipid content is similar on basal and lateral sides

39
Q

transcytosis

A

endocytosis of substances form 1 membrane region, followed by trans cellular transport of vesicles and exocytosis form another membrane region

40
Q

microvilli

A
  • 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
Q

cilia

A

-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
Q

basolateral surface modifications

A
  • in/out folds of basolateral membrane in epithelial cells

- increase SA, seen in cells that transport heavily from basolateral surface

43
Q

basal lamina

A
  • 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
Q

how doe epithelial cells connect to basil laminae?

A
  • hemidesmosomes and focal adhesions

- these connections are formed by integrins

45
Q

epithelial stem cells

A
  • 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
Q

typical cell signaling pathway

A
  • 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
Q

exocrine glands

A

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
Q

endocrine glands

A

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
Q

adeocarcinomas

A

cancers derived from glandular tissue

50
Q

carcinomas

A

epithelial origin cancers

result from defects in regulatory pathways

51
Q

Cystic fibrosis basics

A

-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
Q

typical clinical features of CF

A
  • sinus: chronic sinus infections, nasal pollyps
  • lung: recurrent respiratory infections
  • pancreas: exocrine pancreatic insufficiency
53
Q

How is CF identified?

A
  • mostly in newborn screen
  • at birth with meconium ileus
  • failure to thrive
54
Q

How do you treat CF?

A
  • nutrition
  • targeted lung therapies
  • antibiotic therapies
  • anti inflammatory treatments
  • CTFR modulators
55
Q

basal bodies

A
  • core anchors from which cilia are formed
  • microtubule rich cylinder from 9 triplet microtubules
  • ABC tubules
  • polarized structure
56
Q

axoneme

A
  • structural skeleton of cilium
  • formed from doublet microtubules
  • AB tubules
  • plus end is at ciliary tip
  • provide tracks of movement w/in cilia
57
Q

transition zone

A
  • links basal body to axoneme and ciliary membrane

- limits the diffusion of membrane and soluble protons into/out of the cilium

58
Q

ciliary membrane

A
  • continuous with cellular plasma membrane

- compartmentalized so it is distinct

59
Q

intraflagellar transport (IFT)

A
  • 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
Q

ciliary assembly

A

1-centrioles/basal bodies are assembled

2- formation of cilium

61
Q

centrioles and their connection to cilia

A
  • 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
Q

ciliogenesis

A
  • 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
Q

motile cilia

A
  • required for movement of fluid in respiratory, neural, reproductive tracts
  • produced by axonemal dyne dependent sliding motion
  • 9+2 arrangment
64
Q

non motile/sensory/primary cilia

A
  • possess 9+0 arrangement
  • lack axonemal dyne arms
  • signaling functions
65
Q

what can cilia sense?

A
  • physical stimuli, light, chemical stimuli

- these can all produce downstream effects

66
Q

ciliary node

A
  • 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
Q

extracellular matrix (ECM)

A
  • 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
Q

deep fascia

A
  • tougher region of dense, connective tissue including epimysium of muscles
  • organized into specific functional units (ligaments, joints, tendons, capsules, coverings)
69
Q

functions of connective tissues

A

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
Q

regulatory functions of CT

A
  • 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
Q

resident cells of CT

A

produce and secrete components of ECM, many can proliferate to produce new connective tissue

72
Q

mesenchymal cells

A

precursors to all the connective tissue family members. primarily function embryogenesis

73
Q

fibroblasts

A

pre-eminent cells of most connective tissues in the body

74
Q

myofibroblasts

A

derivatives of fibroblasts are capable of smooth muscle-like function, found in connective tissues that require contractile function. Generated at site of wounds

75
Q

adipocytes

A

derivatives of fibroblasts and or primitive mesenchymal cells. founding adults-store fat as energy for other cell types

76
Q

osteoblasts and osteocytes

A

make bone

77
Q

osteoclasts

A

break down bone

78
Q

chondrocytes

A

make cartilage

79
Q

smooth muscle cells

A

make some of the extracellular matrix components which they are embedded in.

80
Q

immigrant blood-derived cells

A

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
Q

lymphocytes

A

central to acquired immunity to foreign organisms/viruses/materials

82
Q

macrophages

A

large “engulfing” cells that phagocytose: cells, ECM, other non-cellular material. critical regulatory cells that secrete and respond to extracellular signals

83
Q

physiological functions of macrophages

A

engulf invading microorganisms
promote blood vessel formation (angiogenesis)
remodel damaged tissue
remodel normal developing tissue and organs as part of morphogenesis

84
Q

neutrophis and eosinophils

A

important for defense against microorganism

85
Q

mast cells

A

secretory cells that release various responses to immune signals (vasodilators)

86
Q

osteoclasts

A

phagocytic cells that appear to be derived from blood monocytes, similar to macrophages. function in bone resorption

87
Q

fibroblasts

A

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
Q

ECM components

A
  • structural fibers which provide mechanical strength and resiliency
  • hydrated gelatinous material (ground substance) where structural fibers are embedded
  • numerous extracelluar macromolecules
89
Q

collagen

A
  • 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
Q

fibrilar collagen

A
  • 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
Q

fibril-associated collagen

A

-decorate the surface of collagen fibrils, thought to link fibrils to each other tissue components and each other

92
Q

network forming collagen

A
  • 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
Q

loose connective tissue

A
  • thin collagen fibrils that are relatively sparse, arranged in latices
  • cell densities and ground substance components are high in loose connective tissue
94
Q

dense connective tissue

A
  • 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
Q

how is collagen sythesized?

A
  • intracellularly

- secreted and modified extracellularly

96
Q

intracellular synthesis of collagen

A
  • collagen peptides are synthesized on ER and translocated
  • post translationally modified
  • assembled in a triple helix
97
Q

extracellular synthesis of collagen

A
  • 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
Q

elastic fibers

A

-elastin and fibrillin: assemble into stretchable and resilient fibers and sheets

99
Q

elastin

A

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
Q

fibrilin

A

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
Q

ground substance

A
  • made of proteoglycans (GAGs)
  • other secreted proteins and glycoproteins (proteases that process collagen, etc.)
  • inorganic and small organic solutes
  • water
102
Q

proteoglycans

A
  • highly negatively charged
  • rigid extended structure causes them to readily form gels
  • some proteoglycans can bind to and inactivate or activate other proteins
103
Q

what happens when wound occurs?

A
  • 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
Q

bone functions

A

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
Q

differences between bone and cartilage as tissues?

A
  • 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
Q

what are the two main functions of cartilage?

A
  • provide resilient but pliable support structure

- direct the formation and growth of bone

107
Q

chondrocytes

A
  • 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
Q

hyaline cartilage

A
  • collagen that forms thin fibrils arranged in irregular 3D pattern
  • rich in proteoglycans and free glycosaminoglycan hyaluronic acid (promotes hydration/flexibility)
109
Q

structural properties of hyaline cartilage

A
  • 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
Q

elastic cartilage

A

-contains thin collagen fibrils and proteoglycans, distinguished by abundant elastic fibers and interconnecting sheets

111
Q

fibrocartilage

A

-contains large bundles of regularly arranged collagen that is similar to dense regular connective tissue, designed to resist compression and sheer forces

112
Q

is cartilage avascular?

A

Fuck yes. he said this about 8,000 times.

Also know how it grows

113
Q

diaphysis

A

central shaft

114
Q

epiphysis

A

expanded ends

115
Q

spongy bone

A

has thin anastomosing spicules called trabeculae

116
Q

what does bone marrow consist of?

A
  • hematopoietic tissue or adipose

- results in 2 different surfaces: periosteum (dense connective tissue) and endosteum (internal soft tissue with many)

117
Q

osteoprogenitor cells

A

stem cells capable of cell division to generate osteoblasts and osteocytes. present in both personal and endosteal surfaces

118
Q

osteoblasts

A
  • inner layers of both perosteal/endosteal surfaces where bone growth is occurring
  • secrete initial un-mineralized extracellular matrix of bone (osteoid)
119
Q

osteocytes

A
  • 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
Q

osteoclasts

A
  • not related by lineage, derived from monocytes in blood

- reliable and are related to macrophages

121
Q

bone matrix

A
  • most extracellular matrix is calcified/packed with dense parallel collagen fibers
  • contains negatively charged particles
  • mineralized or calcified
122
Q

bone is vascular and innervated

A
  • 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
Q

intramembranous ossification

A
  • 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
Q

endochondral ossification

A
  • within previously made cartilage tissue
  • generates various structures of skeleton that will become bone
  • some cells in perichondrium converted to osteoprogenitors
125
Q

appositional growth

A

growth from within
-in the perichondrium at cartilage surface, mesenchyme/fibroblasts proliferate and differentiate into more chondrocytes which secrete more hyaline matrix

126
Q

interstitial growth

A
  • growth from within

- chondrocytes embedded in matrix continue to proliferate w/in their lacunae and secrete ECM, internal growth

127
Q

replacement of cartilage by bone

A
  • 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
Q

growth of long bones

A
  • long bones grow in length and diameter

- cartilage is critical point for length growth

129
Q

where does bone resorbtion occur?

A

on the endosteal surface

130
Q

how does calcification of the matrix occur?

A
  • 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
Q

how is bone and cartilage regulation mediated?

A
  • 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
Q

control of calcium homeostasis

A
  • calcium mobilization from bone
  • tight regulation from endocrine hormones
  • Parathyroid hormone (bone resorption)
  • calcitonin (stimulates calcium uptake into bone)
133
Q

how much of an increase is there in the number of vessels from the aorta to the blood vessels?

A

2-3 billion fold

500 fold increase in cross sectional diameter

134
Q

how is capillary design different from other vessels?

A

capillaries and post capillaries are designed for exchange, other vessels are designed for mass circulation

135
Q

where is flow the slowest?

A

capillaries and venuoles

136
Q

tunica intima

A

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
Q

tunica medi

A

layer in the middle of a vessel, comprised of multiple layers of elastic laminae, smooth muscle cells, collagen

138
Q

tunica adventitia

A

comprised of collagenous tissue (collagen and elastin). In larger vessels it contains vasa vasorum

139
Q

vasa vasorum

A

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
Q

arteries

A

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
Q

why do arteries have an elastic layer?

A

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
Q

muscular artery layers

A

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
Q

smaller muscular arteries

A
  • 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
Q

arterioles

A
  • 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
Q

metaterioles and arteriole venule shunts

A
  • connect larger arterioles and venules

- vasoconstriction/dilation directs blood flow through/bypasses capillary beds

146
Q

capillaries

A
  • 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
Q

where does most of the molecular traffic btw. vascular system and tissues?

A
  • capillary endothelium, much of the exchange by diffusion

- 2 main capillaries are recognized: continuous and fenestrated

148
Q

fenestrated capillaries

A

pores or fenestrations in the endothelial cells, allow for bulk flow of plasma past endothelial boundary

149
Q

continuous capillaries

A

endothelial cells form uninterrupted lining, although transfer can occur via pinocytotic vesicles

150
Q

sinusoidal capillaries

A

endothelial cells are separated by wide pores (discontinuous) large enough to permit RBC to pass (spleen)

151
Q

post capillary venules

A
  • 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
Q

veins

A
  • thin walled
  • collapsed structures for viewing
  • wall thickness increases with diameter
153
Q

small veins

A
  • intimal layer endothelial cells and no inner elastic lamina
  • media is 2-4 layers smooth muscle
  • adventitia is collagenous
154
Q

medium sized veins

A
  • similar endothelia lining and muscle layer to small veins

- increasing thickening of tunica adventitia (thickest layer)

155
Q

large veins

A
  • 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
Q

how is blood circulated in veins?

A
  • 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
Q

pulmonary arteries

A
  • low pressure function (15-25 mmHg)

- structure is different from systemic arteries

158
Q

lymphatic flow and structure

A
  • 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
Q

anastomoses

A

-connections btw. arteries and veins that permit collateral circulation to occur within tissues

160
Q

end arteries

A

-supply a section of tissue that cannot have an alternate arterial supply (found in lung and kidney)

161
Q

portal systems

A
  • portal systems begin in capillary beds and end in capillary bed
  • found in hypothalamic-anterior pituitary and hepatic portal system
162
Q

pampiniform plexus

A
  • countercurrent arrangement btw. artery and venous network

- spermatic cord for optimal heat exchange

163
Q

three classes of muscle?

A

cardiac, skeletal, smooth

164
Q

muscle histology

A
  • 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
Q

types of skeletal muscle

A

fast (2 types) and slow twitch

  • fast has higher myosin turnover (20xs per sec)
  • slow muscle turns over slower (5xs per sec)
166
Q

cardiac muscle fibers

A
  • single nucleus
  • smaller diameter
  • shorter than skeletal
  • intercalated disc (prevents adjacent cells from pulling apart, contains gap juct.)
167
Q

smooth muscle

A
  • 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
Q

sarcomere

A
  • 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
Q

myofibrils

A
  • bundle of contractile filaments
  • covered with own sarcoplasmic reticulum
  • 2 primary filaments (thin-actin, thick-myosin)
  • 2 regulatory proteins: tropomyosin, troponin
170
Q

thin filaments

A
  • 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
Q

2 types of actin

A

-G actin (globular) or F actin (filamentous)

172
Q

thick filaments

A
  • 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
Q

cross bridge interactions

A
  • 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
Q

smooth muscle contraction

A
  • 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
Q

dystrophin

A
  • 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
Q

titin, nebulin, and alpha actinin do what?

A

-maintain the highly ordered structure of sarcomeres

177
Q

titin

A
  • large protein that links myosin thick filaments to Z line
  • part is bound to myosin (inflexible)
  • keeps filaments centered in sarcomere
178
Q

nebulin

A

-large protein associated with actin, important for keeping thin filaments organized

179
Q

alpha actinin

A

crosslinks actin filaments at the Z line

180
Q

familial hypertrophic cardiomyopathy (FHC)

A
  • 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
Q

events of a single contraction

A
  • 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
Q

how do skeletal muscles contract uniformly and rapidly?

A
  • 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
Q

what 3 molecules are critical for signaling and energy?

A

-Ca2+, O2, ATP

184
Q

what 2 structures have evolved for speed and storage of materials for contraction?

A

transverse tubule system and sarcoplasmic reticulum

-these 2 allow electrical signal to take place everywhere in cell in milliseconds

185
Q

transverse tubule system

A
  • 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
Q

sarcoplasmic reticulum

A
  • each myofibril has “stocking” of SR
  • around the bundle, Ca2+ is stored
  • shortens the distance so diffusion can occur in microseconds
187
Q

Where is Ca2+ stored in the cell?

A
  • intracellular storage compartments, often in the ER (smooth)
  • this is similar to the muscle’s SR
188
Q

how is Ca2+ released from the SR?

A
  • 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
Q

what are the structural components in E-C coupling?

A
  • 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
Q

what does calsequestrin do?

A

-each molecule binds ~50 Ca2+

191
Q

what are the complexes that connect the t-tubule and SR?

A
  • 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
Q

mutations in t-tublue/SR can cause what diseases?

A
  • abnormal Ca release channel=malignant hyperthermia

- no DHP receptor=muscular dysgenesis (E-C coupling is interrupted, death is result)

193
Q

list the sequence of events that occur during a single contraction

A

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
Q

what is the difference between smooth and cardiac muscle for E-C coupling?

A
  • 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
Q

what is the relationship between length and tension for a muscle fiber?

A
  • 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
Q

how many muscles does 1 motor neuron innervate?

A

-1 muscle and a subset of fibers in that muscle

197
Q

how does the size of a motor unit relate to the type of work a muscle does?

A
  • 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
Q

what are the 3 groups of skeletal muscle?

A

slow, fast, intermediate

-virtually all muscles are a mix of these

199
Q

slow oxidative fibers

A
  • postural or maintained contraction

- red due to high myoglobin content

200
Q

intermediate fibers

A
  • fast with glycolitic and oxidative enzymes

- fast twitch=rapid bursts of energy

201
Q

how do skeletal muscles recover from damage from exercise?

A
  • 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
Q

satellite muscle cells

A

-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
Q

how does repair occur in cardiac and smooth muscle?

A
  • 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
Q

what effect does exercise have on muscle?

A

-hypertrophy (new myofibrils added)

conversely if you don’t exercise you atrophy

205
Q

muscle fatigue in exercise

A

-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
Q

smooth muscle innervation

A
  • 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
Q

Hypertrophic cardiomyopathy

A

-autosomal dominant
-heterogeneous
-incomplete penetrance
1/500 individuals

208
Q

Hypertrophic Cardiomyopathy Cellular Consequences

A
  • 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
Q

HCM phenotype in Patients

A
  • 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
Q

if you see a healthy athlete with murmur and SCD what do you think?

A

HCM!!!!!!

211
Q

myostatin and skeletal muscle growth

A

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
Q

malignant hyperthermia

A

-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
Q

what 2 anesthesias cause malignant hyperthermia?

A

halothane, succinylcholine

214
Q

What occurs in a malignant hyperthermia event?

A
  • depolarization
  • Ca2+ channel opens
  • channel does not close
  • muscles cannot stop contracting over and over, go until ATP exhausted
215
Q

clinical signs of malignant hyperthermia

A
  • muscle rigidity, particularly *masseter spasm
  • increased CO2
  • rhabodomyolysis
  • hyperthermia
  • halothane/caffeine test on muscle biopsy
216
Q

if you see someone with masseter spasm and hyperthermia, what do you think?

A

MALIGNANT HYPERTHERMIA!

217
Q

how do you manage malignant hyperthermia?

A
with DANTROLENE (2.5 mg/kg)
-stops spasms, targets RyR receptor and blocks the Ca2+ channel
218
Q

duchenne muscular dystrophy

A

-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
Q

how prevalent is cardiomyopathy in DMD?

A

100% of all cases by adulthood

220
Q

how do you treat DMD?

A

corticosteroids

-prolong independent adulation (has side effects)