Download MCB Lecture 14 – Cell Movement and Muscles

MCB Lecture 14 - Cell Movement
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What G-Protein is involved in Cell Movement?
o Rho-GTPase
When Rho is phosphorylated, what is activated?
o Arp2/3 Complex
What type of cytoskeletal structure starts to polymerize at the leading edge?
o Actin
Rho also activates another molecule. What is this and what does it do?
o Cofilin
o It depolymerizes actin at the trailing edge and reorganization of the
leading edge
Something unique happens in the movement of leukocytes. Before RhoGTPase activates the Arp2/3 Complex for movement, another complex is
activated first. What is this complex?
o WASP
What does Prolifin do in the cell movement pathway?
o It replaces G-Actin-ADP with G-Actin ATP so that it can be added back
to the leading edge.
What is Wiskott-Alrich Syndrome? Mode of Inheritance?
o X-Linked
o It results from a mutation in WASP (expressed only in hematopoietic
cells)  No Arp2/3 Activation
o Leads to a failure of Actin Nucleation  cannot form lamellopodia 
WBC do not migrate to site of infection
o Can do a Bone Marrow Transplant
MUSCLE
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What type of Myosin makes up muscle fibers?
o Myosin II
What are the two filaments that make up a Myofibril? What are these
filaments formed by?
o Thick and Thin Filaments
o Thick Filaments: Myosin Motor Proteins (Motor II)
o Thin Filaments: Actin
What do the Thick Filaments have that allow them to contract?
o 2 ATPase Heads
What is the Contracile Unit of a muscle called?
o Sarcomere
What extends out from the Z-Line of a Sarcomere?
o The – end of actin
What is the M-Line?
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o The middle area of the Sarcomere that is composed of Thick
Filaments. The M-line specifically only contains the Myosin Filaments
but not the Myosin ATPase heads.
What is embedded in the Z-Line?
o The + ends of actin filaments
What proteins are attached to actin filaments?
o Tropomyosin and Troponin
What are the steps involved in muscle contraction?
o Calcium flood into the cell  Binds to Troponin C  Causes Troponin
to displace Tropomyosin  Contraction occurs
Why does Tropomyosin have to be displaced before contraction can occur?
o Because Tropomyosin is blocking the myosin binding site on the actin
filament.
What are T-Tubules?
o Deep invaginations the depolarization travels down the T-Tubules
What is the Sarcoplasmic Reticulum?
o Specialized ER that stores Calcium and has voltage sensitive Ca2+
Channels
When the sarcomere actually moves to contract the muscle, how does it
move? What shortens? What is required?
o The Z-Discs pull closer together, which shortens the Sarcomere and
the muscle contracts.
o ATP is required for the thick filaments to walk along the thin
filaments. ATP is also required for the detachment of myosin heads
from the thin filaments.
Does Myosin walk towards the plus end or the minus end of the thin
filament?
o Plus end
Which filament has a Power Stroke?
o Myosin
How does Rigor Mortis happen?
o After death, the body has no ATP to release the actin, and Ca2+ cannot
be recycled and returned to the SR, so the muscles “lock” in the
constricted position.
What is Dilated Cardiomyopathy?
o Mutations in Actin (Cardiac Muscle Isoform)
 Actin is mutated where it binds to the Z-Disk, leading to
defective contraction, an enlarged heart, and early heart failure
What is Familial Hypertrophic Cardiomyopathy?
o A mutation in Myosin II
o #1 cause of sudden cardiac death among athletes
o Usually asymptomatic until heart hypertrophies to the point where
fatal cardiac arrest occurs.
MUSCULAR DYSTOPHIES
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What is Dystrophin?
o It is a protein that links the actin cytoskeleton of the muscle cell to an
integral membrane glycoprotein. This glycoprotein then links to the
Extra Cellular Matrix.
Why is Dystrophin important?
o Because it transduces contractile forces from the sarcomeres within
one cell to the other cells by sending the signal across the
Extracellular Matrix.
Starting from the Actin Cytoskeleton inside of the Muscle Cell, and ending
with the Extracellular Matrix, list the order of the anchoring proteins that are
involved in this connection.
o Actin Cytoskeleton  Dystrophin  B Dysytroglycan  A
Dystryoglycan  (which both attach to Sarcoglycans)  Laminin 
Extracellular Matrix
When muscle is damaged or diseased, what two cells can repair it?
o Satellite Cells
o Side Population Cells
Which cell type gives the most muscle regeneration?
o Satellite Cells
Where are Side Population Cells derived from?
o Pericytes
What are the 5 types of Muscular Dystrophies?
o Duchenne
o Becker
o Limb Girdle
o Fascio-Scapulo-Humeral
o Emery-Dreifuss
What is Duchenne Muscular Dystrophy? Mode of Inheritance?
o Most common and most severe type
o X-Linked
o Non-functional protein, so NO detectable Dystrophin in muscle AT
ALL.
What is Gower’s Sign?
o When children with Muscular Dystrophies use their arms to stand up.
What is Becker Muscular Dystrophy?
o Caused by a mutation in Dystrophin that causes a partial dysfunction
in the protein.
o You still see some protein showing up, it is just damaged.
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o The severity can be highly variable based on which section of the gene
was mutated.
What is Emery-Dreifuss Muscular Dystrophy? Mode of Inheritance?
o X-Linked
o It is a mutation in Emerin or Lamin A/C that causes a defect in the
lamin assembly of the nuclear envelope.
o Causes early contractures and flexion deformity in the elbows, and
arrhythmias.
In which type of Muscular Dystrophy do you see Gonadal Mosaicsm?
o Duchenne Muscular Dystrophy
Which 4 Muscular Dystrophies are Autosomal?
o Myotonic Dystrophy
o Fascioscapulohumeral Muscular Dystrophy
o Limb Girdle Muscular Dystrophy
o Congenital Muscular Dystrophy
What is Myotonic Dystrophy? Mode of Inheritance? Symptoms?
o Autosomal Dominant
o Trinucleotide Repeat Disorder that keeps getting larger from
generation to generation (anticipation)
o Sustained involuntary contraction of a muscle group
What is Fascioscapulohumeral Muscular Dystrophy? Mode of Inheritance?
Symptom?
o Autosomal Dominant
o Scapular Winging
o Deletion of a Subtelomeric Repeat
What is Limb Girdle Muscular Dystrophy? Mode of Inheritance?
o Autosomal Recessive
o Mutation of Sarcoglycans
o Similar presentation to DMD, but NO COGNITIVE IMPAIRMENT
What is the mutation in that causes Congenital Muscular Dystrophy?
o Laminin
What is the major problem with using Gene Therapy as a DMD Treatment?
o The Dystrophin gene is too large for viral vectors
Stem Cell Therapy can be used to introduce a mini-dystrophin into the
patient. How is Utrophin involved?
o Utrophin is a homologous protein that can be up-regulated to perform
similarly to Dystrophin.