Muscle

Question 1

Properties of skeletal muscle

Answer 1

Long, cylindrical, multi-nucleated cells composed of a repeating alignment of myofilaments that creates a striated appearance; nuclei are located on the periphery of skeletal muscle cells, except for in the case of damaged cells

Skeletal muscle cells can be fast twitch or slow twitch, largely dependent on the density of mitochondria as well as the myosin ATPase gene expressed

Question 2

Properties of cardiac muscle cells

Answer 2

Single nucleated cells (myocytes) separated by intercalated discs, which physically link contracting cells together and form gap junctions for rapid electrical communication & synchronous contraction

Question 3

Properties of smooth muscle cells

Answer 3

Single nucleated, spindle-shaped cells linked by gap junctions

Question 4

Sarcomere

Answer 4

Basic unit of muscle contraction; defined as extending from one Z line to the next Z line;

~10,000 sarcomeres can make up 1 skeletal muscle cell

Question 5

Thin Filaments

Answer 5

Comprised of two filamentous actin strands wound in a helical arrangement

Question 6

Thick Filament

Answer 6

Bundles of 300-400 myosin pairs; myosin is comprised of a pair of heavy chains and two pairs of light chains; heavy chains form globular heads with alpha helical regions and light chains associate with the globular heads; globular heads have both actin binding and ATP binding sites

Question 7

Myosin cycle - skeletal muscle

Answer 7

In the relaxed state, Ca2+ concentration is low and myosin binding sites on actin are covered by tropomyosin

Rising intracellular Ca2+ binds to troponin, inducing a conformational change that is transferred to tropomyosin to allow uncover myosin binding sites on actin; myosin binds actin and immediately “pulls” the actin 8nm forward

ATP binding to myosin triggers it’s dissociation from actin; hydrolysis of ATP by the myosin head ATPase powers the conformational change that “cocks the head” of myosin, preparing it for the next binding cycle

Question 8

Myosin cycle in smooth muscle

Answer 8

Increased intracellular Ca2+ binds Calmodulin and Ca-Calmodulin activates CaM Kinase; CaM kinase phosphorylates one of the myosin light chains, which binds actin to generate force

Ca pumps and Na-Ca exchangers in the sarcolemma remove calcium, leading to inactivation of the kinase and dephosphorylation of myosin by a phosphatase

Question 9

Function of dystrophin

Answer 9

Dystrophin is part of the protein machinery that anchors actin beneath the plasma membrane to extracellular matrix molecules

Question 10

Function of Titin, Nebulin, and a-actinin

Answer 10

Titin links myosin thick filaments to the Z line, keeping myosin centered in the sarcomere

Nebulin and a-actinin associate with actin filaments, maintaining a regular arrangement of the sarcomere

Both proteins contribute to the passive tension in a muscle

Question 11

Mechanism of AP-generated contraction in skeletal muscle

Answer 11

A depolarized nerve axon releases ACh at the neuromuscular junction, which binds AChR in the muscle post-synaptic membrane; AChR is an ion channel that opens, causing depolarization and triggering an AP which propagates in both directions from the endplate toward the tendon, and along the t-tubule network

Depolarization triggers opening of the DHPR channel, a voltage-gated Ca2+ channel in the t-tubule; the DHPR is mechanically coupled to the RyR Ca2+ release channel in the SR, which opens to allow Ca2+ efflux from the SR into the cytoplasm where it initiates actin/myosin interaction

Question 12

Excitation - Contraction Coupling (Skeletal Muscle)

Answer 12

The mechanism by which depolarization in the t-tubule system is translated into Ca2+ release from the SR

Question 13

Termination of Ca2+ signaling

Answer 13

Ca-ATPase pumps in the SR membrane transport Ca2+ back into the SR and bring cytoplasmic Ca2+ back to a low level

Question 14

E-C Coupling (Cardiac Muscle)

Answer 14

In cardiac muscle, Ca2+ entry through the voltage-gated Ca2+ channel in the t-tubule is required to bind the RyR in the SR, triggering it to open and release Ca2+ from the SR into the cytoplasm; this is Calcium Induced Calcium Release (CICR)

Question 15

Motor Unit

Answer 15

Refers to 1 motor neuron and the collection of muscle fibers that it innervates; one motor neuron may innervate multiple fibers but each muscle fiber is only innervated by one motor neuron

Motor unit size varies, from 2-3 fibers (for very fine movements) to 500 muscle fibers (for large muscles)

Question 16

Grading muscle tension (skeletal) - 2 major mechanisms

Answer 16

1. Increase the frequency of action potentials until a maximal (tetanic) contraction is achieved
2. Recruit additional motor units until all motor neurons innervating the muscle are stimulated

Question 17

Satellite Cells

Answer 17

Stem cells that give rise to new myoblasts to repair injured skeletal muscle; damaged cells produce factors such as leukemia inhibitory factor (LIF) to trigger proliferation of satellite cells

Question 18

Effect of exercise on muscles

Answer 18

Exercise causes hypertrophy of muscles; the cross-sectional area of each cell is increased as myoblasts are recruited and new myofibrils are formed

Question 19

Muscle fatigue

Answer 19

Increased organic phosphate and hydrogen ions produced as a result of massive ATP consumption by skeletal muscle leads to decreased Ca2+ release from the SR as well as decreased binding of Ca2+ to troponin, causing fewer myosin-binding sites to be exposed and decreasing the overall efficiency and power of contraction

Question 20

Hypertrophic Cardiomyopathy - Cardiac phenotype

Answer 20

Characterized by thickening & stiffening of the heart wall, especially in the left ventricle; impairs the heart’s ability to fill and pump effectively.

Phenotypic features include:

Cardiomyocyte and cardiac hypertrophy

Myocyte disarray

Interstittial and replacement fibrosis –> arrhythmia

Dysplastic intramyocardial arterioles –> ischemia

Question 21

Molecular defect of hypertrophic cardiomyopathy

Answer 21

Most common mutation is a missense point mutation Asp –> Tyr that may occur in different proteins of the sarcomere complex

Cardiomyopathies are often autosomal dominant, demonstrating incomplete penetrance and genetic heterogeneity;

Question 22

Malignant hyperthermia phenotype

Answer 22

Individuals are healthy throughout life until exposed to anesthesia agents (halothane and/or succinylcholine); this exposure triggers hypermetabolism, hyperthermia, skeletal muscle damage, and death if untreated (70%)

Specific signs: Muscle rigidity (masseter), increased CO2 production, rhabdomyolisis, hyperthermia, acidosis, hyperkalemia, tachycardia

Treatment = dantrolene sodium

Question 23

Molecular defect of malignant hyperthermia

Answer 23

Autosomal dominant mutation in RYR1 gene; leads to prolonged activation of the RyR protein and extended Ca2+ release in the presence of anesthesia agent trigger molecule (halothane and/or succinylcholine)

Question 24

Duchenne Muscular Dystrophy phenotype

Answer 24

Primarily affects boys with onset of skeletal muscle disease at 3-5 years old

Phenotypic characteristics include:

Abnormal gait (i.e. toe walking)
Gower's sign, 
Calf pseudohypertropy
Wheelchair bound by ~11 years old 
Death in 20s by progressive involvement of respiratory muscles 

Becker Muscular Dystrophy is characterized by milder muscular complaints and later-onset cardiomyopathy

Question 25

Molecular defect of Duchenne Muscular Dystrophy

Answer 25

Caused by big deletions (often frameshift) in the X-linked DMD gene coding for dystrophin protein; disrupts the association between intracellular actin within muscle cells and the muscle cell membrane

Question 26

Clinical presentation of hypertrophic cardiomyopathy

Answer 26

Often asymptomatic throughout life BUT may present with dyspnea, angina, syncope, cardiac murmur, or arrhythmia

…also, sometimes sudden cardiac death

Question 27

Myofibril

Answer 27

An association of thick and thin filaments, arranged into sarcomeres which are aligned in series and surrounded by SR

Question 28

Source of Ca2+ for smooth muscle

Answer 28

Smooth muscle cells are very thin; Ca2+ entering from channels in the plasma membrane quickly diffuses to the center of the cell; smooth muscle cells do not need t-tubules or SR

Question 29

Myostatin

Answer 29

Normally made and secreted by muscles as a negative feedback for muscle growth; mutation or selective inhibition leads to increase in muscle mass