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110 Cards in this Set

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Compare ATP production during fed and fasting state
FED STATE - ATP is produced largely from catabolism of muscle glycogen, blood glucose or blood lipids
FASTING - glucose is spared for brain and muscle derives energy from lipids and ketone bodies (and small amount from AA)
What role does muscle play for energy production during fasting
- Provides carbon skeletons of amino acids for gluconeogenesis by the liver in order to maintain blood glucose level
3 types of skeletal muscle fibers
Type I - SLOW OXIDATIVE

Type IIa - FAST OXIDATIVE-GLYCOLYTIC

Type IIb - FAST GLYCOLYTIC
Compare color of skeletal muscle fibers and explain difference
TYPE I and IIa - red, because of high myoglobin content and oxidative capacity

TYPE IIb - white - low myoglobin and low oxidative capacity
Which skeletal fiber muscle type is "slow twitch" and which is "fast twitch" , explain difference
SLOW TWITCH - type I

FAST TWITCH - type IIa and IIb

Speed of contraction is related to ATPase activity of type of myosin present in fiber
Describe type I skeletal muscle fibers
SLOW, RED
- Capable of maintaining low intensity contractions for long periods without fatiguing and produce ATP by oxidative metabolism - present mainly in postural muscles
Describe type IIb skeletal muscle fibers
FAST, WHITE

- Employed in rapid powerful contractions over relatively short periods, produce ATP EXCLUSIVELY by anaerobic glycolysis and can become fatigued very quickly
- Carry stores of glycogen as an instantly available source of glucose so that speed and intensity of response is not limited by delivery of oxygen.
- Muscles of eye and fingers and some limb muscles have high proportion of type IIb fibers
Describe type IIa skeletal muscle fibers
FAST RED
- Intermediate in character between two other types, both carry glycogen store AND posesing oxidative ability
- They fatigue much less easily then type IIb
- Prevalen in skeletal muscles that are involved in regular movement (soleus) rather then those involved in sudden bursts of intense activity
Can you change fiber types of muscle
NO - but you can improve performance of muscle fibers by appropriate training - marathon training can improve performance of type IIa muscles
Metabolism of cardiac muscle is almost totally _ , describe consequences of this
AEROBIC - consequently it is rich in mitochondria and has abundant reserves of myoglobin. It also has small stores of lipids and glycogen - glycogen is only used in extreme circumstances
It can also oxidize wider range of substrates more effectively then skeletal muscle - ketone bodies, lactate
Most of energy of cardiac muscle comes from _
FATTY ACIDS (60-80%)
Smooth muscle obtains most of its energy from _
GLYCOLYSIS but can also do so by oxidation - but not as well as cardiac muscle, also can utilize lactate
ATP under influence of myosin ATPase breaks down into
ADP + Pi
ATP + creatine --> ?
Phosphocreatine + ADP
If an isolated muscle fiber is twitched electronically, no fall in level of ATP is observed - explain why
This is because of reaction catalyzed by CREATINE KINASE

ATP + CREATINE --> PHOSPHOCREATINE + ADP

This reaction is at equilibrium when muscle is at rest - when muscle contracts CK reaction operates from R to L to instantly replenish ATP
Compare ATP production during fed and fasting state
FED STATE - ATP is produced largely from catabolism of muscle glycogen, blood glucose or blood lipids
FASTING - glucose is spared for brain and muscle derives energy from lipids and ketone bodies (and small amount from AA)
What role does muscle play for energy production during fasting
- Provides carbon skeletons of amino acids for gluconeogenesis by the liver in order to maintain blood glucose level
3 types of skeletal muscle fibers
Type I - SLOW OXIDATIVE

Type IIa - FAST OXIDATIVE-GLYCOLYTIC

Type IIb - FAST GLYCOLYTIC
Compare color of skeletal muscle fibers and explain difference
TYPE I and IIa - red, because of high myoglobin content and oxidative capacity

TYPE IIb - white - low myoglobin and low oxidative capacity
Which skeletal fiber muscle type is "slow twitch" and which is "fast twitch" , explain difference
SLOW TWITCH - type I

FAST TWITCH - type IIa and IIb

Speed of contraction is related to ATPase activity of type of myosin present in fiber
Describe type I skeletal muscle fibers
SLOW, RED
- Capable of maintaining low intensity contractions for long periods without fatiguing and produce ATP by oxidative metabolism - present mainly in postural muscles
Describe type IIb skeletal muscle fibers
FAST, WHITE

- Employed in rapid powerful contractions over relatively short periods, produce ATP EXCLUSIVELY by anaerobic glycolysis and can become fatigued very quickly
- Carry stores of glycogen as an instantly available source of glucose so that speed and intensity of response is not limited by delivery of oxygen.
- Muscles of eye and fingers and some limb muscles have high proportion of type IIb fibers
Describe type IIa skeletal muscle fibers
FAST RED
- Intermediate in character between two other types, both carry glycogen store AND posesing oxidative ability
- They fatigue much less easily then type IIb
- Prevalen in skeletal muscles that are involved in regular movement (soleus) rather then those involved in sudden bursts of intense activity
Can you change fiber types of muscle
NO - but you can improve performance of muscle fibers by appropriate training - marathon training can improve performance of type IIa muscles
Metabolism of cardiac muscle is almost totally _ , describe consequences of this
AEROBIC - consequently it is rich in mitochondria and has abundant reserves of myoglobin. It also has small stores of lipids and glycogen - glycogen is only used in extreme circumstances
It can also oxidize wider range of substrates more effectively then skeletal muscle - ketone bodies, lactate
Most of energy of cardiac muscle comes from _
FATTY ACIDS (60-80%)
Smooth muscle obtains most of its energy from _
GLYCOLYSIS but can also do so by oxidation - but not as well as cardiac muscle, also can utilize lactate
ATP under influence of myosin ATPase breaks down into
ADP + Pi
ATP + creatine --> ?
Phosphocreatine + ADP
If an isolated muscle fiber is twitched electronically, no fall in level of ATP is observed - explain why
This is because of reaction catalyzed by CREATINE KINASE

ATP + CREATINE --> PHOSPHOCREATINE + ADP

This reaction is at equilibrium when muscle is at rest - when muscle contracts CK reaction operates from R to L to instantly replenish ATP
Which muscle enzyme operates to maintain ATP levels and prevent accumulation of ADP - give reaction
ADENYLATE KINASE (also called myokinase)

2ADP --> ATP + AMP
Which enzyme removes AMP product and helps pulling AK reaction to the right in favor of ATP production
AMP DEAMINASE

AMP + H2O --> IMP + NH3
Product of ammonia in AMP deaminase reaction is important - why?
It INHIBITS action of enzyme ADENOSINE DEAMINASE thus maintaining adenosine levels - this offers muscle an advantage since ADENOSINE IS VASODILATOR and increases blood flow

ADENOSINE + H2O --> INOSINE + NH3
Initial ATP production is achieved by _
SWITCHING TO GLYCOLYSIS - mitochondrial activation producing ATP by respiratory chain takes longer
In type IIa and IIb muscle fibers glucose substrate for glycolysis comes from where?
GLYCOGEN stores - especially in vigorous contractions
What activates glycogen breakdown in muscle
CALCIUM IONS release from SR during contraction activate GLYCOGEN PHOSPHORYLASE - controlling enzyme in glycogen breakdown (also pyruvate dehydrogenase and controlling TCA enzymes )
AMP, Pi and NH3 all activate _
PFK I - controlling enzyme of glycolysis
In times of stress what activates muscle processes even more potently?
EPINEPHRINE
McArdles disease results from what
Its a glycogen storage disease resulting from genetic defficiency of MUSCLE GLYCOGEN PHOSPHORYLASE - results in unusual fatigue and painful muscle cramps on exercise
ATP can be produced from what substrates
CARBOHYDRATE + LIPID
At rest major source of ATP is _
LIPID except after a high carbohydrate meal
During intense exercise whats major source of ATP
CARBOHYDRATE (over short periods glycogen in fiber types IIa and IIb)
Carbohydrate has several advantages over fat as substrate for ATP - what are they
- In catabolism it can be switched on faster
- Yield of ATP per oxygen is greater
- Maximum rate of ATP formation is greater
Carbohydrate as source of ATP has one major disadvantage - what is it
It produces about 7 times less energy per gram - partly because it stored hydrated - we have overcome this problem by having small stores of glycogen for use in extreme situations requiring high power output
What is unique about IIb type skeletal muscle fibers metabolism
- They have LOW OXIDATIVE CAPACITY so their metabolism is largely restricted to ANAEROBIC GLYCOLYSIS
Oxygen Debt
- In absense of oxygen, reoxidation of NADH from glyceraldehyde dehydrogenase step of glycolysis is achieved by converting pyruvate to lactate. In prolonged exercise, lactate accumulates, it is a "dead end product", which ultimately must be converted to pyruvate and NADH re-oxidized by respiratory chain. This requires oxygen - thats why we heavily breath at the end of vigorous exercise - this is called OXYGEN DEBT
Cori cycle
Lactate can diffuse out of muscle and be transported to liver where it can be converted to glucose by gluconeogenesis. If this glucose is released into the blood stream, then it can be taken up again by muscle and catabolized by glycolysis back to lactate - CORI CYCLE
Muscle fatigue is directly due to accumulation of lactate - T/F
FALSE
One of the possible factors of fatigue in muscle is fall in pH - what effect would it have
- Decrease in activity of PFK1 (controlling enzyme in glycolysis)
- Inhibition of Ca release from SR
Which factor is important in SLOW FATIGUE of muscle
- INCREASE IN Pi LEVELS - probably the most significant factor overall - has metabolic effects of E/C coupling and depletion of glycogen
Fatigue of muscle probably could have a neuromuscular component - T/F
TRUE - inability to synthesize Ach at adequate rate could be reason
How do you explain central fatigue
INCREASED TRYPTOPHAN levels in brain lead to INCREASED LEVELS OF SEROTONIN which promotes RELAXATION AND SLEEP.
Why do drinks for athletes contain a lot of branched amino acids
They compete with tryptophan for the same transporter in brain and by inhibiting amount of tryptophan you decrease relaxation and sleepiness
How do we replenish glycogen levels
Controlling enzyme for glycogen synthesis is GLYCOGEN SYNTHETASE. Insulin released in response to intake of glucose, activates glycogen synthetase. (G-6-P also stimulates its non-active form)
How can you increase muscle glycogen content
Appropriate training and high carbohydrate diet can increase muscle glycogen content (slightly)
At rest type I and IIa fibers produce their ATP from _
LIPID and GLUCOSE - mostly lipid except after high carbohydrate meal
Sources of exogenous lipids
Fatty acids bound to albumin (from adipocytes) and triacylglycerols (forming the core of VLDL and chylomicra)
Muscles containing higher proportion of red fibers have higher LPL activity - T/F
TRUE
Triglycerides are hydrolyzed by _
LPL - lipoprotein lipase present on surface of vascular endothelial cells
How do fatty acids get into cell
Appear to diffuse freely into cell. Fatty acid binding protein (FABP) is present in muscle cell (especially heart muscle and red muscle) which assists transport within cell
Fatty acid oxidation is switched on by _
Redox state (NAD+/NADH ratio)
Lipolysis is switched on by _
EPINEPHRINE and GLUCAGON
At rest type I and IIa muscle fibers preferentially use _ as fuel
FATTY ACIDS
At rest muscle fibers I and IIa use fatty acids as fuel to spare glucose - how do they achieve that
At normal resting plasma concentrations fatty acids diffuse into muscle cell and are catabolized to acetyl CoA which inhibits pyruvate dehydrogenase. Acetyl CoA is then converted to citrate (1st step of TCA cycle) whic inhibits PFK - controling step of glycolysis. G-6-P - substrate for PFK reaction accumulates and inhibits uptake of glucose in muscle cell
Why does glucose become main fuel in muscle after high carbohydrate meal
Raised blood glucose level will stimulate release of insulin which inhibits lipolysis - blood lipid level falls and GLUCOSE TAKES OVER as the main source of ATP production
Describe importance of AA metabolism in energy production
- Normally contributes little as energy source for ATP in muscle in fed state. In some cases metabolism of branch chain amino acids can contribute up to 20% ATP supply in resting muscle
In fed state heart ontains all its energy from _
lipid and glucose (mostly fatty acids) by OXIDATIVE METABOLISM
How does heart obtain energy under extreme energy demands circumstances
- It can utilize lactate produced by white muscle fibers (type IIb) and can take up extra glucose - facilitated by tissues high in hexokinase.
- Heart also has small store of glycogen from which it can derive energy under very extreme circumstances
In early stages of fasting major source of energy is _
Why is this important
FATTY ACIDS - reserves glucose for brain and RBC which cannot oxidize fat
What becomes major energy source at initial stage of STARVATION
KETONE BODIES - produced by liver - especially acetoacetate and beta-hydroxybutyrate
As fasting is prolonged (4-5 days) what becomes fuel source for muscle
- Muscle decreases its use of ketone bodies - becomes major source of energy for brain - depends mainly on FATTY ACIDS FOR FUEL
Role of muscle in gluconeogenesis
In starvation DEGRADATION OF MUSCLE PROTEINS provides carbon skeletons of AMINO ACIDS for GLUCONEOGENESIS in liver. This is vital role for maintenance of brain function
Define glucogenic amino acids
AMINO ACIDS that can be CONVERTED TO GLUCOSE
Define ketogenic amino acids
AMINO ACIDS that are OXIDIZED to produce energy
Two amino acids that are MOSTLY RELEASED by muscle
ALANINE
GLUTAMINE
Define muscular dystrophies
Group of genetically determined progressive primary disorders of muscle - arise from muscle disorder NOT from neuropathy, etc
Most prominent clinical manifestations of muscle dystrophies
Progressive muscular weakness and loss of muscle tissue
Name X linked muscular dystrophies
- Duschenne (DMD)
- Becker (BMD)
- Emery-Dreifus (EDMD) - rare
Autosomal muscular dystrophies
- Myotonic
- Facioscapulohumeral dystrophy
-Limb Girdle MD
- Bethlem myopathy
Name 3 most common muscle dystrophies
Most common is DMD (1 in 3500), followed by Myotonic dystrophy (1 in 8000) and Facioscapulohumeral (1 in 20000)
Most severe and most common muscular dystrophy is _
Duschenne
Beckers is different from DMD is that it is _
Milder form, characterized by later onset and slower progression
Describe DMD
Individuals with DMD appear relatively normal at birth but begin to show signs of impaired muscle function by the time they begin to walk. Calf muscles appear enlarged due to pseudohypertrophy in which normal muscle fibers are replaced by fat and connective tissue. Patients are generally confined to wheelchair by the age of 10 and typically survive until late teens or early twenties
Gene responsible for DMD and BMD is located _
on the short arm of X chromosome
Gene responsible for DMD and BMD encodes for _
DYSTROPHIN
Describe dystrophin difference in BMD and DMD
In DMD - LITTLE OR NO FUNCTIONAL DYSTROPHIN (99 % no dystrophin)

in BMD - DYSTROPHIN REDUCED IN AMOUNT or ALTERED in SIZE
Describe genetic defect in dystrophin gene in DMD
DELETIONS and DUPLICATIONS generally SHIFT THE READING FRAME and cause DMD
Describe genetic defect in dystrophin gene in BMD
Normally associated with NON-FRAMESHIFT MUTATIONS
Biochemical basis of DMD and BMD
DYSTROPHIN - intracellular protein which appears to be part of complex joining intracellular cytoskeleton to extracellular matrix
- Appears to interact with actin and beta-dystroglycan - which in turn interacts with collagen and laminin in ECM.
- Defficiency of dystrophin may lead to increased fragility of dystrophic muscle and possible permeability to Ca ions
Diagnosis and carrier detection of DMD
- Serum creatine kinase is markedly elevated (50-100 times normal) - generally elevated in carriers, can overlap with normal range
Both CARRIER DETECTION and FETAL DIAGNOSIS can be achieved by testing DNA employing PCR
Describe Emery-Dreifus MD
- X LINKED OR AUTOSOMAL
- MILDER then DMD, rarer
- Onset - 1st or 2nd decade, SLOW PROGRESSION
- Contractures, muscle wasting - upper limb abd calf muscles
- Impairment of cardiac conduction (2-nd-4th decade) and be life threatening
- CK levels are normal to moderately elevated
Genetic and biochemical basis of Emery-Dreifus MD
- Caused by mutations in genes encoding PROTEINS OF NUCLEAR ENVELOPE

EMD I - X LINKED RECESSIVE - more common - mutation in gene encoding EMERIN

EMD II - AUTOSOMAL DOMINANT OR RECESSIVE (rare) - mutation in gene encoding LAMINS A OR C
Describe overal autosomal muscular dystrophies
- More numerous collectively although some types are extremelly rare
- MYOTONIC and FACIOSCAPULOHUMERAL dystrophies are AUTOSOMAL DOMINANT and LIMB GIRDLE - group of dystrophies some of which can be AUTOSOMAL RECESSIVE OR DOMINANT
Describe MYOTONIC MUSCULAR DYSTROPHY
- Also called Steinerts disease
- DOMINANTLY INHERITED - most common form of muscular dystrophy affecting adults, symptoms do not appear until adolescence and progression is slow.
- ANTICIPATION - tendency for disorder to be expressed earlier and become more severe from generation to generation
- Characterized by MUSCLE WASTING, beginning in face (MASK LIKE FACE with drooping eyelids), neck and hands and MYOTONIA - inability of muscle to relax after contraction, it also affects cardiac and smooth muscle and is associated with early cataracts, immunoglobulin abnormalities, DM, testicular atrophy, frontal balding in men and often mild mental retardation
- 3 groups - late onset, classical adult onset or congenital (most severe)
- CK VALUES NORMAL
Genetic basis of MYOTONIC MUSCULAR DYSTROPHY
- 2 specific molecular defects - DM1 and DM2
- DM1 RESULTS FROM TRINUCLEOTIDE EXPANSION of CTG (or GCT) repeat, it has been mapped to CHROMOSOME 19. This repeat is also known as "TRIPLET REPEAT EXPANSION"
- Normal individuals have 5-35 copies of repeat, affected - 50-1000 - correlated with severity and age of onset
- DM2 results from tetranucleotide expansion of CCTG repeat in non-coding region of ZNF9 gene on chromosome 3
Anticipation in MYOTONIC MUSCULAR DYSTROPHY
- These large repeats are meiotically unstable and susceptible to further mutation giving rise to increase in number of repeats - early onset and severity of disease - anticipation of increased effect on subsequent generatons
Biochemical basis of MYOTONIC MUSCULAR DYSTROPHY
DMPK gene encodes protein kinase enzyme known as myotonin protein kinase - affected individuals may be at risk for anesthetic induced malignant hyperthermia
Diagnosis and prenatal diagnosis of MYOTONIC MUSCULAR DYSTROPHY
Molecular diagnosis by PCR using primers that flank the CGT repeat sequence - if expansion is too large use Southern blotting
Fascioscapulohumeral dystrophy
- Variable and relatively benign muscular dystrophy also showing AUTOSOMAL DOMINANT INHERITANCE - occurs in about 1 in 20000 men and women and AFFECTS UPPER BODY (DMD and BMD - legs)
- SYMPTOMS ARE VARIABLE IN AGE OF ONSET, EXTENT AND SEVERITY - symptoms are mild, progress slowly and life expectancy normal (20% become eventually wheelchair bound)
- Symptoms include facial muscle weakness followed by weakness of upper arms that may progress to legs
- CK LEVELS range BETWEEN NORMAL AND 5 FOLD ELEVATION
Limb-girdle muscle dystrophy
- Muscle weakness affecting both upper arms and legs - can be both AUTOSOMAL DOMINANT AND RECESSIVE
- RECESSIVE FORMS ARE MORE FREQUENT and ONSET IN CHILDHOOD or TEENAGE YEARS
- DOMINANT forms usually PRESENT IN ADULTHOOD
- Muscles affected initially - PELVIC AND SHOULDER GIRDLES
- Most common forms caused by mutation in genes encoding SARCOGLYCANS - either missing or defficient
- CK LEVELS RANGE FROM NORMAL(dominant forms) TO VERY HIGH (recessive)
Congenital muscular dystrophy
- Group of autosomal recessive muscular dystrophies where symptoms appear at or soon after birth
3 types - merosin negative, merosin positive and neuronal migration disorder
Merosin negative congenital muscular dystrophy
- Deficiency of merosin - important component of basal lamina
- Degree of severity of symptoms depends on specific mutation
- Progression slow, brain can also be affected
Merosin positive congenital MD
Merosin is present but other proteins are missing - consequence of range of mutations in other genes
Congenital MD with NEURONAL MIGRATION DISORDER
- Usually accompanied by severe mental retardation
- FUKUYAMA CMD occurs only in Japanese and is the result of mutation in gene encoding FUKITIN - expressed in brain and nervous tissue
- This is severe form of MD
CK levels for congenital MD
MODERATELY HIGH for all three forms
OCULOPHARYNGEAL MD
- Usually AUTOSOMAL DOMINANT (rarely recessive) with onset of symptoms later in life (40-50 years old) , characterized by DROOPING EYELIDS and WEAKNESS in FACIAL and PHARYNGEAL MUSCLES, can also extend to limbs
- Most common in FRENCH CANADIANS (1 in 1000) and Bukhara Jews in Israel
Biochemical basis for OCULOPHARYNGEAL MD
- EXPANSION OF GC repeat encoding polyalanines with gene encoding poly A binding protein, presence of extra AA causes protein molecules to clump in cell nuclei
- CK levels are NORMAL or MILDLY ELEVATED
BETHLEM MYOPATHY
- Rare AUTOSOMAL DOMINANT MD first observed in Dutch families
- Onset usually before age of 5 but can vary
- SYMPTOMS - PROXIMAL MUSCLE WEAKNESS affecting both legs and arms and JOINT CONTRACTURES - elbows and ankles
- CK levels are NORMAL or SLIGHTLY ELEVATED
- Can be caused by one of several different MUTATIONS in chromosome 21 in genes encoding TYPE VI COLLAGEN
MALIGNANT HYPERTHERMIA
- MOST FEARED COMPLICATION OF GENERAL ANESTHESIA
- More common in children and is a genetic predisposition affecting skeletal muscle
- Affected individuals show SEVERE REACTION TO CERTAIN ANESTHETICS and also some muscle relaxants with pathological elevation of Ca ions in SR
- This causes MUSCLE RIGIDITY, ELEVATION OF BODY TEMP, ACIDOSIS AND TACHYCARDIA
- Used to be fatal in 80% of affected people now with dantrolene which reduces Ca release from SR - fatality is 10%
Biochemical bases of MALIGNANT HYPERTHERMIA
- OPENING OF DEFECTIVE CA RELEASE CHANNEL appears to be prolonged in presence of certain drugs - Ca floods SR
- This stimulates muscle ATPase causing muscle rigidity
- Ca ATPase pump works more then needed trying to pump back Ca to SR and consuming ATP
- ATP, CO2 and heat is produced - acidosis, heat, muscle rigidity
- Cell membrane can become leaky because of insufficient ATP