MUSCLE

Question 1

What differential diagnosis should be considered when a young, otherwise healthy person drops dead?

Answer 1

Hypertrophic cardiomyopathy.

[Cardiac myocytes don’t work as well as they ought to, so more filaments are added to each cell. # cells does not increase, only the size and number of filaments within each cell]

Question 2

What is the muscle cell phenotype in hypertrophic cardiomyopathy?

Answer 2

1) hypertrophic cardiac myocytes
2) myocyte disarray
3) interstitial and replacement fibrosis (propensity to arrhythmia)
4) dysplastic intramyocardial arterioles (ischemia)

Question 3

What type of mutation generally causes hypertrophic cardiomyopathy?

Answer 3

Missense mutation in structural genes.

Question 4

What are the epidemiological outcomes for persons with HCM?

Answer 4

Most are fine. Some have angina, syncope, dyspnea. BUT, some will drop dead. <1%/year

Question 5

Clinical Presentations HCM?

Answer 5

– Cardiac murmur (if LV outflow obstruction)
– Cardiac ‘Pump’ Failure (dyspnea, angina)
– Arrhythmia (syncope/sudden death)
– Sports/Family screening

Question 6

Diagnosis?

Answer 6

Echocardiogram, EKG, MRI, Family history, genetic testing, chest‐X ray.

Question 7

What is the inheritance?

Answer 7

Autosomal dominant.

Question 8

How do muscles increase in size?

Answer 8

Length: recruit myoblasts (add nuclei)
Girth: recruit myoblasts and increase size and number of myofibrils (add sarcomeres)

Question 9

What are the muscular cows lacking? Talk about that

Answer 9

Myostatin.
– Normally made and secreted by muscles as a negative feedback for muscle growth
– May be raised in AIDS patients with muscle wasting

Question 10

Describe the steps in myostatin processing.

Answer 10

Mature myostatin produced after dimerization and cleavage. Inactive myostatin is bound to follistatin. Binding of dimerized myostatin (now unbound from follistatin) to Activin receptor IIB leads to Smad (tx factor) activation and changes in gene expression.

Question 11

Malignant hyperthermia is what mode of inheritance? What causes the condition?

Answer 11

Genetic environmental disorder. Must be exposed to anasthetics.

Autosomal dominant. RYR1 mutation (70%).

Question 12

Which anesthetic agents trigger malignant hyperthermia?

Answer 12

Halothane

Succinylcholine

Question 13

What is the prevalence of malignant hyperthermia?

Answer 13

1/5000 - 1/100,000.

600 deaths/year in US

Question 14

What is the presentation of malignant hyperthermia?

Answer 14

hypermetabolism, skeletal muscle damage, hyperthermia.

70% mortality if left untreated

Question 15

Describe the cascade of events leading to malignant hyperthermia?

Answer 15

Stimulus (depolarization) travels down nerve, into muscle cell through t-tubule and through DHP receptors which trigger Ca channel opening (RyR). Ca channel does not close, causing a prolonged contraction. ATPase pumps Ca back into the SR continuously, generating massive amounts of heat.

Question 16

Specific clinical signs of MH?

Answer 16

Masseter spasm on induction of anesthesia
Increased CO2 production
Hyperthermia
Rhabdomyolysis

[non specific: metabolic acidosis, tachycardia, tachypnea, hyperkalemia]

Question 17

Can diagnose MH with what lab test?

Answer 17

Halothane/caffeine test. Requires a muscle biopsy.

Question 18

Immediate treatment for MH?

Answer 18

Give DANTROLENE. 2.5 mg/kg

[Bicarbonate; Cool patient (refrigerated saline), gastric lavage, surface cooling, treat arrhythmias, hyperventilate]

Question 19

Duchenne muscular dystrophy inheritance?

Answer 19

X-linked recessive.

1/3500 males. Mutation in dystrophin gene (DMD).

Question 20

Clinical signs and symptoms of Duchenne Muscular Dystrophy?

Answer 20

Onset @ 3-5 years. Abnormal gait.

Toe walking, Gower sign, calf pseudohypertrophy

Reproductive fitness 0, wheelchair bound by mid teens at lates.

Question 21

What is the lab value indicative of DMD?

Answer 21

High creatinine kinase (1000s)

Normal range <200

Question 22

What is the treatment?

Answer 22

corticosteroids

[pulm therapy, walking devices, supportive care, etc.]

Question 23

What are the levels of muscle unit, from smallest to largest? Which is defined as a “cell”

Answer 23

myofilament (myosin/actin) < myofilament (cell) < muscle fiber < muscle fasiculus (fascicle)

Question 24

What defines a sarcomere?

Answer 24

Z line — Z line (from Z to shining Z)

Question 25

Describe the binding cycle of myosin/actin. Include ATP hydrolysis, power stroke, troponin, tropomysin, Ca, and ADP/Pi in your answer.

Answer 25

Myosin is bound by ATP, unconnected to actin. Tropomysin covers the myosin binding site on the actin molecule. Calcium levels rise, uncovering the myosin binding site. Myosin binds actin and immediately undergoes the power stroke, releasing ADP/Pi as it does so. Myosin remains bound to actin until ATP binds the myosin head, releasing it from actin and allowing the myosin to reset in the “cocked” position. This process continues until the Ca levels in the cell decrease ant the muscle stops firing.

[myosin head is an ATPase]

Question 26

What muscle type(s) are linked by gap junctions?

Answer 26

Smooth, cardiac

Question 27

What is the phenomenon described as E-C coupling?

Answer 27

An action potential travels through a motor neuron and into the plasma membrane of a muscle cell. It travels down the t tubule and somehow couples to release Ca from the SR. The t tubule and SR, however, are not cytoplasmically linked.

Question 28

What receptor in the t-tubule links with the SR to provide the EC coupling? What is it?

Answer 28

The DHPR (dihydropyridine receptor) is a voltage-gated Ca channel

Question 29

What receptor in the SR membrane links with the t-tubule to provide E-C coupling?

Answer 29

RyR (ryanodine receptor)

[The present theory is that depolarization causes a conformational change in the DHP receptor that in turn causes the calcium release channel to open and Ca flows out of the SR.]

Question 30

What is a distinguishing feature of cardiac muscle? What functions does it serve?

Answer 30

Intercalated disc.

1. join cells together for contraction
2. gap junctions

Question 31

Describe the muscle stroke in smooth muscle. What differentiates this from a skeletal muscle contraction?

Answer 31

increased calcium binds calmodulin, calmodulin binds CaM kinase, CaM kinase phosphorylates one of the myosin heads, and the phosphorylated myosin binds actin and force is generated. Ca is pumped out (Ca pump and Na/Ca exchanger). Low calcium inactivates the kinase, myosin is dephosphorylated by a phosphatase.

[smooth muscle cells are small enough that Ca diffusion can do the job without the elaborate SR system. however, this contraction is slow compared to skeletal muscle]

[smooth muscle can remain in a state where myosin is bound to actin continuously without any ATP expenditure. Think…sphincters]

[smooth muscle contains no troponin]

Question 32

Each ____ is surrounded by sarcoplasmic reticulum.

Answer 32

Myofibril

Question 33

Each motor neuron innervates ____ muscle and in that muscle it innervates a subset of the total muscle fibers. The muscle fibers innervated by a motor neuron are termed the _____. It is a unit because each time the motor neuron fires an action potential all the muscle fibers innervated by the neuron contract in unison.

Answer 33

one; motor unit

Question 34

What cells help in muscle repair? Are they inside the muscle cell or outside? What types of muscle have these cells?

Answer 34

Satellite cells spawn myoblasts which help with muscle repair. closely associated, but outside.

Cardiac has none. Skeletal does. Smooth muscles don’t either. They de-differentiate, divide and repair themselves.

Question 35

In which muscle type is extracellular Ca required for contraction?

Answer 35

Cardiac.

[smooth contracts w/o. due to coupling of DHPR/RyR in skeletal muscle]

Question 36

How is tension increased in skeletal muscle?

Answer 36

1) Increased frequency of AP

2) increased motor unit recruitment

Question 37

How is tension increased in smooth muscle?

Answer 37

1) hormones and neurotransmitters

2) length-tension

Question 38

What is the effect of exercise?

Answer 38

You ADD myofibrils. Myofibrils can’t get bigger in size b/c they are diffusion limited (each wrapped by SR). So the muscle fibers get bigger by adding myofibrils of identical size. Remember, a myofibril is a bundle of myosin and actin with its own Ca storage.

Question 39

IL-6 is secreted by muscle cells and exercise increases secretion (not LO i think)

Answer 39

x

Question 40

LIF (leukemia inhibitory factor) induces proliferation of satellite cells. (not LO i think)

Answer 40

x

Question 41

Irisin is released by muscle and increases energy expenditure by changing fat cells into brown-fat-like cells. In mice it reduces diabetes and obesity. (not LO i think)

Answer 41

x