Muscle Contraction Flashcards
1
Q
What is the contractile unit of a muscle cell?
A
sarcomere
2
Q
Hundreds of what form the thick filament of the myofibril
A
myosin II (motor protein)
3
Q
Describe the structure of myosin II
A
2 ATPase heads
heavy chain tail
4
Q
Describe how the myosin II arrange themselves on the actin filaments
A
tails face the middle (bare zone or M line), heads protrude out in both directions
5
Q
What covers up the myosin binding sites on actin thin filaments?
A
tropomyosin (with troponin bound to it)
6
Q
When calcium is released, where does it bind to initiate muscle contraction?
A
troponin
7
Q
The location where tails of thick filaments are embedded is called:
A
M line
8
Q
What is a sarcomere?
A
One Z line to next Z line
9
Q
What is brought closer together during muscle contraction?
A
Z lines
10
Q
What is the structure of a thin filament?
A
double helix of actin monomers, tropomyosin wound around it.
11
Q
In an electron micrograph the dark line in the middle of the white section is what?
A
Z disk
12
Q
What contracting in muscle cell?
A
myofibril
13
Q
In the sarcomere, F-actin is often ____
A
capped
14
Q
What caps the positive end of F-actin in sarcomere?
A
Cap Z
15
Q
What caps the - end of F-actin in sarcomere?
A
Tropomodulin
16
Q
Describe muscle contraction
A
Nerve signal triggers action potential in muscle cell membrane, spreads into T-tubules (membrane invaginations), then across gap junctions to sarcoplasmic reticulum
→ release of Ca2+
Ca2+ binds troponin C, lifts troponin I from actin
→ displaces tropomyosin
Myosin head can now bind
“walks” forward. Sliding model. POWER STROKE
17
Q
What is the sarcolemma?
A
plasma membrane of muscle cell
18
Q
What is the sarcoplasmic reticulum?
A
specialized sER for calicium storage in muscle cells
19
Q
Myofibrils are made of overlapping:
A
thick and thin filaments
20
Q
What two things are needed for contraction of muscle cell
A
calcium, ATP
21
Q
What is required to release the myosin head from actin thin filament?
A
ATP
22
Q
Describe the power stroke, or the steps involved in myosin heads walking along actin in muscle contraction
A
calcium - troponin leaves trypomyosin so myosin heads can bind
ATP causes release of a head
hydrolysis - ADP
myosin head moves forward and binds, pulling sarcomere closer together
23
Q
What is the driving force behind the myosin power stroke?
A
ATP hydrolysis
24
Q
Myosin walks toward where?
A
+ end of actin
25
Explain rigor mortis
No ATP so myosin can't release from actin
26
Key words: mutation where actin binds Z disk, early heart failure is what disease?
Dilated cardiomyopathy
27
Symptoms of CHF develop gradually; dyspnea, weakness, fatigue, palpitations, ankle edema; risk of PE and sudden death is what disease?
Dilated cardiomyopthy
28
What is the mode of inheritance for dilated cardiomyopathy?
30% is hereditary
29
Describe the mechanism for dilated cardiomyopthy
Mutated actin where it binds to Z disk → defective transmission of force in cardiac myocytes → early heart failure
30
Where is the defect in dilated cardiomyopthy?
Mutated cardiac isoform of actin where binds to Z disk
31
What is the spring like protein that anchors thick filaments into z disk?
titin
32
What is the most commonly mutated protein found in dilated cardiomyopthy?
Titin
33
Key words: angina, fatigue, main cause for sudden cardiac death in athletes is what disease?
Familial Hypertrophic Cardiomyopathy
34
Characteristics: asymptomatic/mild symptomatic; dynspnea, angina, palpitation, syncope, fatigue, fatal cardiac arrest (5-10%); #1 cause for sudden cardiac death in athletes is what disease?
Familial Hypertrophic Cardiomyopathy
35
What is the mechanism for Familial hypertrophic cardiomyopathy?
Defective cell migration
36
What is the mode of inheritance for familial hypertophic cardiomyopathy?
AD
37
Where is the defect in familial hypertrophic cardiomyopathy?
Myosin II motor protein (70%), tropomyosin, troponin
38
What is the name of one muscle cell?
myofibril
39
Each myofibril is composed of many
sarcomeres
40
What is the function of dystrophin?
Helps keep shape of muscle cell membrane. Helps transport force from muscle contraction to ECM
41
Describe the shape of dystrophin
very long and straight
42
What is dystrophin attached to (GENERALLY)?
Actin-cytoskeleton & integral membrane glycoprotein complex
43
What does the integral membrane glycoprotein complex that dystrophin attaches to interact with?
ECM (laminin, collagen)
44
What specific things is dystrophin attached to?
actin, dystroglycans, synaptrohins, dystrobrevin
45
Dystrophin helps link the actin cytoskeleton to what?
laminin-2
46
Beta dystroglycan binds to what?
dystrophin & alpha dystroglycan, GRB2
47
What does alpha dystroglycan bind?
ECM, glycoprotein (laminin), proteoglycan (agrin)
48
What is the function of the sarcoglycan complex?
help with binding & recruitment of alpha dystroglycan, they are very important for structural stability of whole protein complex
49
Absence of dystrophin means what?
loss of DAP at sarcolemma (DAP is dystrophin associated protein) → absence of physical link → fragile sarcolemma
50
If a person doesn't have dystrophin what happens with repeated movement?
muscle degeneration
51
What is the name of the cell that performs the majority of muscle repairs and regeneration?
satellite cells
52
Where are satellite cells located?
in basal lamina that surrounds every cell
53
What activates satellite cells?
stress or trauma
54
What kind of division do satellite cells undergo?
asymmetric division
55
Explain the asymmetric division that satellite cells do when they divide?
they divide into another satellite cell & into a myoblast
56
Stem cells (side population cells) differentiate into what?
haematopoetic cells & satellite cells
57
What gives rise to a new myoblast?
satellite cell
58
In MD, why is there CT and fat accumulation?
The stem cells cannot keep up with the demands of all the damaged muscle cells. Satellite cells have telomeres with a certain length so they only have so much dividing capability, MD wears them out
59
List the 3 steps absence of dystrophin will do to a cell
↑ susceptibility to contraction-induced injury
Repeated degeneration-regeneration & ongoing inflammation & necrosis
Eventual muscle destruction
60
The earlier the age of onset, the:
faster the progression
61
What is an enzyme found inside muscle cells that is involved with storage of ATP in cells?
serum creatine kinase
62
key words: onset of muscular weakness at 3-5 y/o, mild cognitive impairment, absence of dystrophin, pseudohypertrophy is what disease?
Duchenne Muscular Dystrophy
63
what does DMD stand for?
Duchenne Muscular Dystrophy
64
Characteristics: Most common & most severe MD; progressive; normal at birth, onset muscle weakness at 3-5 y/o, gower’s sign, calf psuedohypertrophy (insufficient repair response of satellite cells causes accumulation of CT & fat), lordosis & scoliosis, contractures, mild cognitive impairment, respiratory & cardiac musculature impairment; pelvic girdle muscles ! shoulder girdle muscles; wheelchair bound by 10-12 y/o; rare survival beyond 20-30 years; most death due to respiratory or cardiac failure is what disease?
Duchenne Muscular Dystrophy
65
What is the mode of inheritance for Duchenne Muscular Dystrophy?
X linked (2/3 from carrier mother, 1/3 new mutation)
66
What is mechanism for Duchenne Muscular Dystophy?
Mutation causes complete absence of dystrophin in muscle → loss of DAP at sarcolemma & fragile sarcolemma → increased susceptibility to contraction-induced injury → repeated degeneration-regeneration & ongoing inflammation & necrosis → eventual muscle destruction; progressive muscular weakness & atrophy → increase serum creatine kinase
67
Where is the defect in Duchenne Muscular Dystrophy?
Xp21 dystrophin mutation -- complete absence of dystrophin (frameshift insertion/deletion, partial deletion, point mutation)
68
Most of the time the deletion in DMD is what kind?
frameshift
69
Which is the most common and most severe degenerative skeletal & cardiac muscle disorder?
DMD
70
What is the second largest known gene?
dystrophin
71
What disease does dystrophin partly function?
BMD
72
How many exons are in the dystrophin gene?
79
73
How many promoters are in the dystrophin gene?
7
74
Why is there a high incidence of mutation in dystrophin gene?
There is a lot of Interspersed intronic repetitive sequences
75
In BMD there can be variable what?
symptoms
76
Why does a pt with DMD have calf pseudohypertrophy?
Looks like pt has massive calf muscle. Its enlarged b/c of repeated degeneration and accumulation of muscle tissue and fat.
77
The majority of pts with DMD end up dying from what?
respiratory failure
78
what percentage of pts with DMD die from repiratory failure?
70%
79
If a pt with DMD doesn't die from respiratory failure, they are probably going to die from what?
cardiac failure
80
What is the purpose of checking the serum creatine kinase levels if you suspect a pt has MD?
will tell you if there's cell rupture
81
If you suspect pt has MD you can run western blot with what kind of antibody?
dystrophin
82
Describe the western blot of a normal person vs. a pt with DMD or BMD
DMD won't have any lines b/c they don't have any dystrophin. BMB extra lines and in different location - they have abnormal dystrophin.
83
Why is spectrin used when running a western blot for dystrophin?
It is used as a control to make sure protein has actually been extracted from the tissue.
84
What can be used to confirm a pt has DMD?
PCR deletion screen
85
Explain how PCR deletion screen can confirm DMD
Conformation of diagnosis, 18 exons out of 79 exons account for about 98% of deletions we find. So you will do PCR to flank the 18 exons that are usually deleted.
86
If a women is carrier for DMD will she show symptoms?
Usually not
87
What percentage of women carriers of DMD will show symptoms?
8%
88
What are women carriers who show symptoms of DMD called?
manifesting heterozygotes
89
Why will women who are carriers for DMD show symptoms?
random x-chromosome inactivation
90
Key words: dystrophin mutation, late childhood onset, variability are what disease?
Becker Muscular Dystrophy
91
What does BMD stand for?
Becker Muscular Dystrophy
92
Characteristics: Onset late childhood/adolescence, slower progression than DMD, significant variability of symptoms determined by type of mutation in gene stand for what disease?
BMD
93
What is the mechanism for Becker Muscular Dystrophy?
Mutated dystrophin → aberrant but partially function dystrophin protein (milder disease form); progressive muscular weakness & atrophy → increase serum creatine kinase
94
What is the mode of inheritance for BMD?
X-linked
95
Where is the defect in BMD?
Mutation in dystrophin – presence of protein but mutated (inframe insertion/deletion
96
How has BMD helped find treatments for pts with DMD?
Has allowed us to see what deletions are survivable and what part of dystrophin gene is necessary. Has helped scientists find "important" dystrophin domains. Has allowed them to make a mini dystrophin that can be cloned into cells for gene therapy
97
Key words: emerin, sudden cardiac or respiratory failure are what disease?
Emery-Dreifuss Muscular Dystrophy (EDMD)
98
What does EDMD stand for?
Emery-Dreifuss Muscular Dystrophy
99
Characteristics: Onset early childhood, early contractures (elbows, ankles, neck) – flexion deformity of elbows & reduced joint mobility; slowly progressive muscle weakness & atrophy; upper arms & lower legs ! shoulder & hips; cardiomyopathy, conduction defects, & arrhythmias are what disease?
EDMD
100
What is the mechanism for Emery-dreifuss MD?
Defects in lamin (IF) assembly/attachment to nuclear envelope → fragile NE → affects physically stressed tissues, particularly muscle fibers
101
What is the mode of inheritance for EDMD if defect is in emerin?
X-linked
102
What is mode of inheritance for EDMD if defect is in lamin A/C?
AD or AR
103
Where is the defect in EDMD?
Mutation in Emerin (X-linked); Lamin A/C (autosomal dominant/recessive, rare)
104
Key words: myotonin protein kinase, CTG repeat disorder, anticipation, multisystemic, slowly progressive
are what disease?
Myotonic Dystrophy
105
Characteristics: Common; multisystemic disorder; onset 20-40 y/o (any age birth to old age); myotonia = sustained involuntary contraction of muscle group; weakness: hands, legs (gait abnormalities), SCM; atrophy of fascial muscles → ptosis & haggard appearance are what disease?
Myotonic Dystrophy
106
What is the mechanism for myotonic dystrophy?
Pathogenesis not well understood; anticipation – with each successive generation, the repeat disorder expands causing increase in severity of mutation/symptoms each other generation
107
What is the mode of inheritance for myotonic dystrophy?
AD
108
Where is the defect in myotonic dystrophy?
Myotonin protein kinase; trinucleotide repeat disorder (CTG)
109
If a pt has myotonin dystrophy, what will happen as the pt has offspring, and they have offspring, etc.?
More repeats every time the chromosome goes through a germline.
110
Key words: expressionless, ptosis, normal life expectancy, winged scapula are what disease?
Facioscapulohumeral Muscular Dystrophy
111
Characteristics: Rare; onset 10-40 years (95% by age 20); inability to puff cheeks; initial facial weakness (expressionless), ptosis; progressive weakness of face, scapula, & upper arms → difficulty raising arms → winged scapula are what disease?
Facioscapulohumeral Muscular Dystrophy
112
What is the mechanism for Facioscapulohumeral Muscular Dystrophy ?
Not well understood
113
What is the mode of inheritance for Facioscapulohumeral Muscular Dystrophy ?
AD
114
Where is the defect for Facioscapulohumeral Muscular Dystrophy ?
Deletion of subtelomeric tandom repeat (4q35) or t4q;10q
115
What are the two different kinds of limb girdle MD?
type 1 and type 2
116
Which Limb girdle MD is more rare?
type 1
117
key words: sarcoglycan mutation, no cognitive impairment, no pseudohypertrophy, no contractures are what disease?
Limb Girdle Muscular Dystrophy (LGMD 2)
118
Characteristics: Weakness of proximal musculature; “limb girdle” – hip & shoulder; onset 10-20 years old; slower (& variable) rate of progression; severe disability within 20-25; death often from respiratory failure; pseudohypertrophy & contractures rare; no cognitive impairment are what disease?
Limb girdle muscular dystrophy 2
119
What is the mechanism for limb girdle muscular dystrophy 2?
Defective assembly of sarcoglycans → disrupted interaction with dystroglycan protein complex → disrupted association of sarcolemma with ECM
120
What is the mode of inheritance for limb girdle muscular dystrophy 2?
AR
121
Where is the defect for Limb girdle MD 2?
Mutation (alpha-, beta-, gamma-, delta-) sarcoglycans
122
What does LGMD stand for?
lamb girdle muscular dystrophy
123
Is the heart affected in LGMD?
No
124
Key words: onset at birth, laminin mutation, mental retardation is what disease?
Congenital Muscular Dystrophy
125
Characteristics: General muscle weakness, respiratory insufficiency, contractures, seizures, mental retardation; clinically variable is what disease?
Congenital Muscular Dystrophy
126
What is the mechanism for congenital muscular dystrophy?
Imparied myogenesis, synaptogenesis, & mechanical stability
127
What is the mode of inheritance for Congenital muscular dystrophy?
congenital
128
Where is the defect in congenital muscular dystrophy?
Mutation in laminin (of basal lamina)
129
Where does laminin bind?
alpha dystroglycan of cell membrane.
130
Are there any cures for MD?
No
131
What is the general treatment for MD?
supportive: Physical therapy, pacemaker (EDMD & MD(
132
Describe the myoblast transfer for treating DMD
inject donor muscle precursor cells into dystrophic host
133
What are the challenges for gene therapy for DMD? (3)
Dystrophin gene too large for viral vectors
Many cells must contain the gene to improve muscle strength (muscle cells non-dividing)
Immune rejection of cells infected by vector
134
Describe the clinical trial for stem cell therapy for treating DMD
multipotent pericyte-derived cells, from blood vessels of adult skeletal muscle (can differentiate into myoblasts → myotubes)
Systemic delivery of cells, genetically engineered to express mini-dystrophin
Navigate & differentiate into skeletal muscle
Take pts own cells and genetically enginerer them to express mini-dystrophin. Clone it into pts own cells, reinject cells back into pt, they will migrate to muscle damage and then will repair the damaged muscle, newly formed cells will express some dystrophin. By doing stem cell therapy pt will not be cured, but they will be changed from pt with DMD to a pt with milder like becker MD. Pts life will be radically improved.
135
multipotent perycite derived cells can be triggered to differentiate into what?
satellite cells & other cells
136
Where is utrophin expressed?
fetus
137
Describe how upregulation of ultrophin can help treat DMD
Utrophin – expressed in fetus. Expression is shut off and dystrophin takes over. If they upregulate utrophin where dystrophin isn’t produced it can take on some function of dystrophin.
138
Describe how Gene transfer & exon skipping
| could help treat pts with DMD
Antisense oligonucleotide
Blocks exon spice sites to “skip” mutation/deletion
DMD → BMD
139
Describe how the drug PTC124/Ataluren can help treat DMD
Pt has DMD has frameshift mutation in exon 4 – could design oligonucleotides that bind to exon donor and acceptor sites of exon 4 so that exon 4 is not spliced into the mature mRNA, so you skip over the exon that contains the mutation. So you don’t completely cure a pt, will convert pt with DMD to pt with a form of BMD.
Ataluren is in advanced trials. It would treat about 15% of cases with DMD and could also treat some CF. it’s a drug that inhibits nonsense-mediated RNA decay, so as ribosome complex goes over mRNA, normally if ribosome encounters premature stop codon, it stops translation. By binding of this drug to the ribosomal complex, it prevents ribosome from reading it as a stop codon. So it will read through it and translate the rest of the protein. The cases that are caused by premature stop codon could be cured by this drug.
