1 - Biochemistry Flashcards
The immediate source of energy for muscle contraction is?
Which enzyme is involved?
ATP—–>ADP + Pi
Myosin ATPase
What does creatine kinase (CK) have to do with muscle contractions?
Transformation form ATP + Creatine to Phosphocreatine + ADP, and vice versa
What does adenylate kinase (AK) have to do with muscle contractions?
Helps with transforming from 2ADP to ATP +AMP and backwards
What are the energy sources for smooth muscle? major and secondary
Most from glycolysis
Can also use lactate
What is the preferred energy substrate used by cardiac muscles? Which others can be used?
Metabolism is almost totally aerobic
Preferred: Fatty Acids
Others: Glucose, Ketone Bodies, Lactate
In the replenishment of ATP following muscle contractions, which enzyme is activated by AMP?
Glycogen phosphorylase B - glycogenolysis initiated
In the replenishment of ATP following muscle contractions, which enzyme is activated by AMP, Pi, and NH3?
Phosphofructokinase-1 - glycolysis initiated
In the replenishment of ATP following muscle contractions, which enzyme is activated by ADP?
Isocitrate Dehydrogenase - TCA cycle initiated
In the replenishment of ATP following muscle contractions, which enzyme is activated by Ca++ ions? (4)
Glygogen phosphorylase (glycogenolysis active) Pyruvate dehydrogenase (glycolysis/TCA active) Isocitrate dehydrogenase (TCA active) Oxoglutarate dehydrogenase (TCA active)
Describe McArdle’s Disease
A type V glycogen storage disease
Deficiency in muscle glycogen phosphorylase
Myopathy due to defective glycogen breakdown
Painful cramps and fatigue with exercise
*no lactate increase during exercise (abnormal)**
*PRIOR ingestion of sucrose is beneficial
What enzyme releases fatty acids from chylomicrons and VLDL?
Lipoprotein lipase
Why are serum fatty acid levels decreased following increased blood glucose levels?
Insulin is secreted in raised blood glucose - insulin inhibits lipase responsible for releasing fats
By what mechanism is most energy produced in Type I and IIa fibers?
oxidative metabolism
By what mechanism is most energy produced in Type IIb fibers?
WHITE FIBERS
glycogen mobilized for rapid release of substrate
lactate via ANEROBIC GLYCOLYSIS
What is the major disadvantage of carbohydrate metabolism?
It is stored as hydrated form, so it produces about 7 times less energy per gram
What happens to the lactate produced by white (IIb) muscles metabolism?
It goes to the liver to be used in gluconeogenesis (CORI CYCLE)
What is most likely the major contributor to muscle fatigue?
Increase in Pi
What are the 2 big theories that try to explain muscle fatigue? Describe them..
Increase in Pi – self explanatory (major contributor)
Fall in pH - inhibiting PFK-1 and SR release of Ca+
What is the major pathway of glycogen replenishment?
INSULIN activates glycogen synthase (b form to a)
G-6-P presence does the same thing
What are free fatty acids bound to in serum?
Albumin?
Red fibers have a higher level of two certain proteins than white? Which has to do with their preference for oxidative metabolism? What proteins are important?
Fatty Acid Binding Protein (FABP) Lipoprotein Lipase (LPL)
How does increased fat (spare) glucose?
Increased free fatty acids (B-oxidation) inhibits PFK-1, so less breakdown of glucose… Refer back to picture slide..
Describe how AMP stimulates the uptake of fatty acids into mitochondria
REVIEW PICTURE FOR ANSWER
Recall what happens in starvation (4 Points)
- Glucose is reserved for brain
- Muscle uses fatty acids and ketone bodies
- Muscles provide amino acid C-skeletons for liver to use in gluconeogenesis
- Amino acids largely released as alanine and glutamine
Does glucagon activate glycogen phosphorylase in muscle?
NO, survival mechanism in early man. Need energy to kill stuff in a starvation situation. So glycogen is saved for movement
Major muscle fuel after 4h starvation?
Fatty acids
Major muscle fuel after 1-2 days?
Fatty acids + Ketone Bodies
Major muscle fuel after 3 weeks?
Fatty acids
What hormone stimulates the breakdown of muscle protein to provide C-atoms for liver gluconeogenesis during days 1-2 in starvation?
Cortisol
This decreases after day 2 as ketone bodies take over as major fuel source
Excess acetyl CoA is converted to _____ (3) by liver mitochondria?
Acetoacetate
B-hydroxybutyrate
Acetone
How does the muscle utilize ketone bodies as a fuel?
Ketone bodies are converted back to 2 molecules of actetyl CoA….. Enzyme? REVIEW Figure near end of lecture
Muscle breakdown in starvation yields mainly which 2 amino acids?
What is the major site of metabolism?
- Alanine and Glutamine
2. Branched-chain amino acids
What is the major pathway of catabolism for cardiac muscle in the fed state
Oxidative (95%), mostly fatty acids, some glucose
Can oxidize lactate under extreme circumstances
Which glucose transporter is important for uptake of glucose into cardiac muscle (response to insulin)
GLUT-4
Insulin also stimulates PFK-2 to produce F-2,6- bisphosphate
What happens in cardiac muscle metabolism during ischemic conditions?
(eg. MI)
ATP levels fall, AMP levels rise
Anerobic glycolysis is stimulated to compensate for the loss of aerobic ATP production via 2 AMP-mediated mechanisms.
What are the 2 AMP mediated mechanisms of energy production in ischemic cardiac muscle?
Note: goal of both is to activate PFK-1
- AMP activates AMPK - AMP-activated protein kinase which phosphorylates PFK-2. PFK-2 increases production of fructose-2,6-bisphosphate —> activeates PFK-1
- AMP activates PFK-1 directly (via allosteric binding)
Review picture on slide
What are the 2 important X-linked dystophies?
Duchenne (DMD)
Becker (BMD)
THE REST ARE AUTOSOMAL
What population is Oculopharyngeal Muscular Dystrophy (OPMD) prevalent?
French-Canadians
Describe the etiology of DMD
30% new mutations
Dystrophin gene virtually absent
Cause by frameshift mutations (e.g - deletion/duplication)
Describe the etiology of BMD Becker
<2% new mutations
Reduced or Modified Dystrophin gene
Caused by point mutations(not frameshift like DMD)
Where is the dystrophin gene located?
What is it important for?
X chromasome (dont worry about detail) Codes for the dystrophin protein which is important for linking cytoskeletal proteins to transmembrane glycoproteins which connect to the ECM.
What is used in the diagnosis and carrier detection for MD?
HIstory and Physical ****SERUM CREATINE KINASE** Muscle biopsy Multiplex PCR SCAIP (useful in prenatal diagnosis, internal primer sequencing)
Describe the etiology of myotonic muscular dystrophy (MMD or DM - dystrophia myotonica)?
Autosomal dominant
MOST COMMON MD
Affects heart, smooth muscle, CNS, eye, and endocrine system
Caused by a repeat expansion*****
Appears after adolescence, displays anticipation as well (more severe expression generation to generation)
Symptoms of MMD?
Myotonia Muscle Wasting Cataracts Diabetes Mellitus Frontal Balding Mild Mental Deterioration Testicular atrophy *reveiw pic of muscles generally affected (mostly extremities and neck +diaphragm)
In MMD, what is the difference between DM1 and DM2?
DM1 - is more common (98%), shows anticipation, chromosome 19 (More details??)
DM2 - unlikely, milder in presentation, chromosome 3, no anticipation?
Onset/Death in DM1 classic case?
Onset: 10-30 yrs
Death: 48-55 yrs
Onset/Death in DM1 congenital case?
Onset: birth - 10 yrs
Death: 0-45 yrs
Note mild version shows up (20-70yrs) and can live (60yrs-normal)
Mechanism of MMD diagnosis?
Targeted mutation analysis: PCR to find repeat sequence, Southern blot for larger expansions
Describe Facioscapulohumeral Dystrophy (FSHD)
Autosomal dominant Principally affects upper body Defect in long arm of chromosome 4 Onset usually 10-25 yrs old Non-symmetrical pattern of weakness, scapular winging, slight scoliosis
Describe Limb-girdle Muscular Dystrophies (LGMD)
Autosomal dominant AND recessive
Caused by mutations in genes encoding sarcoglycans 4 most common forms
CK levels normal to very high (in some recessive forms)
Describe oculopharyngeal musculodystrophy (OPMD)
Autosomal dominant
Caused by an expansion of GCN repeat within the gene encoding the poly(A) binding protein (PABPN1)
Characteristic drooping eyelids, weakness in facial and pharyngeal muscles - can extend to limbs
CK levels are usually normal or mildly elevated
Describe Congenital Musculodystrophy (CMD)
Autosomal recessive, presenting soon after birth
Hypotonia followed by muscle weakness
50% *Due to a deficiency in laminin-2, while others due to defective glycosylation of alpha-dystroglycans (muscle fiber destruction due to impaired binding of laminin)
CK levels usually moderately high
Describe Bethlem Myopathy
Autosomal dominant, usually onset before 5
Mutation affecting Collagen - VI
Proximal muscle weakness (mild to progressive)
Lifespan not affected
Malignant Hyperthermia (MH)
Feared (Rare) complication of general anesthesia
DMD, BMD, MMD patients may be particularly susceptible
Pathologic release of Ca++ in response to anesthesia
Hypermetabolic Sate
What is the treatment for Malignant hyperthermia (MH)
dantrolene sodium
