Energy Metabolism Of Muscle Flashcards
ATP to ADP and vise versa mechanisms
When ATP is used by muscles, a hydrolysis cleaves the gamma (y) phosphate from ATP, generating energy and ADP
ADP is regenerated to ATP via phosphatases.
GLUT proteins
Glucose transporters that span membrane and conduct facilitated diffuse without ATP.
Has 5 different types for specific tissues
GLUT 1 is in what tissues?
Erythrocytes, blood barriers (brain, retinal, placental and testis)
-High affinity
GLUT 2 is in what tissues?
Liver, kidney, pancreatic (b)-cells,
Intestinal mucosa cells
High-capacity, low affinity
GLUT 3 is found in what tissues?
Brain and neurons.
- main transporter of glucose in nervous system
- High affinity
GLUT 4 is found in what tissues
Adipose tissues, heart muscle, skeletal muscle
- insulin sensitive, high affinity transporters.
- up-regulates in the prescience of insulin
- high affinity
GLUT 5 is found in what tissues?
Intestinal epithelium & Sperm
- technically a fructose transporter*
- high affinity.
Type 2 diabetes
Developing insulin resistance causes GLUT 4 transporters to be deficient and not up-regulate in the presence of insulin.
Phosphofructokinase-1 characteristics
Irreversible reaction in glycolysis (glucose is stuck in glycolysis)
Rate-limiting and committed step
Inhibited by high concentration of ATP and citrate
Activated in muscle by high concentration of AMP
Activated in liver by high concentration of F 2,6 Bisphosphate
Hexokinase characteristics
Found in most tissues especially muscle (NOT liver)
Inhibited by high G6P concentrations
High affinity for glucose (low Km)
Low maximal Velocity (Vmax)
Very efficient enzyme
Normal Lactate production in muscle
Occurs via a build up of anaerobic glycolysis. (Specifically exercising skeletal muscle)
Usually transported to the liver and metabolized back to glucose via cori cycle (gluconeogenesis) to be used again in glycolysis
Why is glucose immediately transformed into glucose 6-P when entering cell?
glucose 6-P cannot escapes the cell. All can be used when needed
- no transporters
examples of Abnormal lactate production in muscle
Hypoxia in muscles or extreme lactic acidosis
Types of lactic acidosis
Normal lactate (<2mmol)
Hyperlactermia (2-5mmol) w/ metabolic acidosis
Lactic acidosis (4-5mmol) without metabolic acidosis
Substrate level phosphorylation produces how much ATP?
2 ATP
Oxidative phosphorylation of one pyruvate produces how many ATP?
10 ATP
Pyruvate dehydrogenase complex (PDH)
Breaks down pyruvate into Acetyl CoA with 3 enzymes and 5 coenzymes
FAD coenzyme is produced by what?
Niacin (Vit B3)
NAD coenzyme is produced by what?
Riboflavin (Vit B2)
Coenzyme-A (CoA) is produced by what?
Pantothenic acid (Vit. B5)
Thiamine pyrophosphate (TPP) is formed by what?
Thiamine (Vit. B1)
Lipoamide is formed by what?
Naturally synthesized by human cells (does not need an essential vitamin)
Three enzymes of the PDH complex
E1 (pyruvate carboxylase)
E2 (dihydrolipoyl transacetylase)
E3 (dihydrolipoyl dehydrogenase)
Glucokinase
Similar to hexokinase except is found in liver.
Also has a higher Km and higher maximal Vmax
not as efficient however in excess glucose, is better than hexokinase
PDH complex regulation
Activated by increased concentrations of
- Pyruvate, NAD+, ADP, Calcium, CoA
Inhibited by increased concentrations of
-Acetyl CoA, NADH, ATP
Can be allosterically inhibited by phosphorylation and activated by dephosphorylation
Irreversible steps of Citric acid cycle (TCA)
Citrate synthase
Isocitrate dehydrogenase
(A)-ketoglutarate dehydrogenase complex
Citrate synthase activation and inhibition
High OAA concentrations =. Activates
High Citrate concentrations = inhibits
Isocitrate dehydrogenase activators and inhibitors
Inhibited by: high concentrations of ATP and NADH
Activated by: high concentrations of ADP and calcium
(A)-ketoglutarate dehydrogenase complex activators and inhibitors
Inhibited by: High succ-CoA concentrations
Activated by: High calcium concentrations in muscles
Adenylate kinase (Myokinase) function in Fatty acid oxidation
Takes 2 ADP molecules and generates 1 ATP and 1 AMP molecules
- quick way to generate ATP and signal the muscle cells to produce Malonyl-COA de carboxylase and allow FAs to enter muscle cells.
Overall fatty acid oxidation steps in muscle cells
Albumin or other carriers carry FAs into cytosol.
FAs are activated into fatty-CoA which is transported to outer mitochondrial membrane via conversion into fatty acylcarnitine by carnitine.
Fatty acylcarnitine is transported into the inner mitochondrial membrane and converted back into fatty-CoA
Fatty CoA is oxidized in inner mitochondrial membrane into multiple Acetyl-CoA
Regulations of fatty acid oxidation in skeletal muscles
Occurs via disabling transferring of fatty acid into mitochondria
- excess citrate from Citric Acid cycle can leave and produce Malonyl-CoA via ACC-2 enzyme which inhibits fatty acid transferring into the mitochondria
- occurs when high ATP
- Malonyl-CoA decarboxylase activates when ATP is Low (high AMP) and reverses the above reaction.
Mobile components of ETC
Coenzyme Q
Cytochrome C
Cardiolipin
Two glycerol molecules esterfied through phosphate bonds
Exclusive to the inner mitochondrial membrane
Maintains the structure and function of the ETC complexes 1-4
Coupling in normal mitochondria
ATP synthesis is coupled to the electron transportation through the complexes.
- every 4 protons generates 1 ATP
Uncoupling in normal mitochondria
Back flow of electrons down the complexes without ATP generation
-importaint for thermogenesis
Can be natural or synthetic
Natural uncoupling
Uses uncoupling proteins localized in inner mitochondrial membrane
UCP 1 = found in brown adipose tissue
UCP 2-5 = found in every other tissue
Synthetic uncoupling
Uses synthetic uncouplers that are chemical that increase the permeability of the inner mitochondrial membrane to electrons
- aspirin is the mot well known
Inhibitors of complex 1 in ETC
Amytal and Roterone
Inhibitor of complex 3 in ETC
Antimycin C
Inhibitors of complex 4 in ETC
Carbon monoxide (at the end of complex 4 to oxygen)
Cyanide and sodium azide (at the beginning of complex 4)
Glycogen storage in both the liver and muscle respectively
100g and 400g respectively
Muscle has more glycogen however liver is more concentrated
Products of glycogenlysis in both liver and muscle
Blood glucose in liver (transported to muscles to be used)
ATO, lactate and CO2 in muscle cells (glucose is actually broken down all the way)
What two bonds are present in glycogen?
(A) 1,4 and (a) 1,6 glycosidic bonds.
Why are glycogen branches important?
(A) 1,6 creates branches on glycogen which are used for two reasons.
1) to increase the solubility of glycogen molecules
2) increase number of non reducing ends and allow for fast synthesis and degradation
Phosphoglucomutase
enzyme used to generate G1P from G6P in glycogenesis
Glycogen synthase
Generate UDP-glucose form G1P in glycogenesis
rate-limiting step of glycogenesis
Transferase (branching enzyme)
Binds glucose-UDP molecules to the chain of glycogen making it longer
Glycogenin
Primer for glycogen synthesis.
Is the starting molecule for creating a new glycogen strand.
Tyrosine is the attachment point on glycogen for UDP glucose
Glycogen phosphorylase
Enzyme for glycogenolysis which breaks (a) 1,4 bonds
Rate limiting regulatory step found only in muscle and liver tissues
Debranching enzyme
Same activity as glycogen phosphorylase except targets (a) 1,6 bonds.
Glycogen phosphorylase activation and inhibition in muscles
Activated by high concentrations of
- AMP
- Ca2
- Epinephrine
Inhibited by high concentrations of
- Insulin
- Glucose 6-P
- ATP
Glycogen synthase activation and inhibition in muscles
Active by large contractions of
- Glucose 6-P
- Insulin
Inhibited by large concentrations
- Epinephrine
Glycogen synthase inhibition and activation in liver
Active by large concentrations of
- G6P
- Insulin
Inhibited by large concentrations of
- Glucagon
- Epinephrine
Glycogen phosphorylase activation and inhibition in liver
Activation occurs in high concentrations of
- Epinephrine
- Glucagon
Inhibition occurs in high concentrations of
- G6P
- Glucose
- ATP
- Insulin
Lysosomal (a) 1,4-glucosidase
Product of a housekeeping gene
Degrades Glycogen at optimal pH of 4.5
Deficiency causes Type 2 Pompe disease
Type 2 Pompe disease
Lysosomal disease caused by deficiency of (a) 1,4 glucosidase in muscle cells
- causes excessive glycogen build up in lysosomes and leads to muscle weakness and cardiomegaly
- appear large inclusion bodies in lysosomes in histology slides
- fatal in infantile form and treated by replacement therapies
Type 5 McArdle syndrome
Deficiency of muscle glycogen phosphorylase enzyme in skeletal muscle only
Myoglobinuria and mygolbinemia can be present
Causes accumulation of glycogen in skeletal muscle fibers (can be seen in staining)
Relatively benign and chronic condition.
Type 6 Hers disease
Liver glycogen phosphorylase deficiency
- causes mild hypoglycemia since glycogen can’t be broken down, however gluconeogensis is still conducted.
- also causes hepatomegaly and cirrhosis of the liver if untreated.
Type 3 cori disease
Deficiency in debranching enzyme
Can’t break down (1) 1,6 glycogen bonds
- causes hypoglycemia and abnormal glycogen structures
- left uncheck produces hepatomegaly and myopathy
Inhibitors of Complex 5
Oligomycin
Cytochrome C
Acts on caspase to initate apoptosis.
CPT - 2 deficiency
Mutation in the carnitine transporter that disables fatty acid COA from entering the mitochondria preventing oxidation.
Autosomal recessive
3 forms
Leather neonatal
Severe infantile
Mild myopathic
Insulin affects on muscle
Turns on AkT and inhibits glycogen degradation as well as turns on glycogen synthesis
Epinephrine affects on muscle regulation
Turns on adenylate Cyclase which initiates the following signal cascade
1) produces cAMP
2) cAMP turns on protein kinase A
3) protein kinase A both turns off glycogen synthase and activates phosphatase A
* Reciprocal regulation*
4) generates G1P and G6P which turns into lactate and ATP
Allosteric regulation of calcium in muscle
Free calcium in muscles bind to calmodulin.
Calmodulin activates phosphorylase kinase B
phosphorylase kinase B stimulates glycogen degradation.
Type 4 Andersen disease
Branching enzyme deficiency in muscle
Causes infantile hypotonia, cirrhosis and death
Glycogen having few branches is the pathological confirmation
CPK/CK 1
Creatinine kinase founds only in the Brain
CPK/CK 2
Creatinine found only in the Heart
presence in blood/urine signals a myocardial infarction
CPK/CK 3
Creatinine kinase found in both skeletal and cardiac muscle
Type 2 oxidative muscle fibers
Fast-twitch red fibers
High myoglobin content and use oxidation to generate energy
Average resistance to fatigue
Large fiber diameter (2nd fastest movement)
Type 2 glycolytic muscle fibers
Fast-twitch white fibers
Low myoglobin concentration appears white.
Fast-glycolytic fibers
Easily fatigued and not energy efficient
Used for sprinting/ quick explosive movements
Very large fiber diameter (fastest movement)
Type 1 muscle fibers
Slow-twitch red fibers
High myoglobin concentration appears red
Slow-oxidative fibers
Very high resistance to fatigue
Used for prolonged aerobic activities
Small fiber diameter (slow speed)
Myoglobin
Similar structure to hemoglobin however can only bind 1 oxygen molecule (heme molecule).
Found in skeletal and heart muscle
High affinity than hemoglobin and becomes saturated quicker.
AMP activates what in muscles?
GLUT 4 transporters
FA transporters
Glycogenolysis and glycolysis
Ca2+ activates what?
Glycogenolysis
PDH complex activation
CTC cycle
Timing of both creating phosphate and ATP in exercise
creatine phosphate =. 5-20 sec
Glycolysis = 20 sec - 2 min
-creatine phosphate is only used for the first minute or so until storages run out. At this point ATP (muscle muscle glycogen) becomes fuel source until exhaustion
Carbs and FA usage in exercise
Carbs: used in vigorous contractions and explosive forces
Fatty acids: used in low intensity exercises
Aerobic vs anaerobic exercise
Aerobic:
- increases aerobic capacity by increasing mitochondria in fast fibers
- utilizes Fatty acids
- uses nutrients from blood
- primary protein in mechanisms is PGC-1a
Anaerobic:
- increases muscle size and number
- utilizes carbs, creatine kinase and glycogen
- does not require external fuels from bloods
- myostatin is a special hormone protein that inhibits protein synthesis up to a certain point (prevents over hypertrophy)
The athlete paradox
Lipid droplet accumulation in muscle cells that are used as energy actually cause increased insulin sensitivity in athletes rather than insulin resistance.
Sarcopenia
Age-related skeletal and muscle mass decline/function
Affects nearly 50% of all 70+ people.
Idiopathic etiology and is multifactorial
Cachexia
Wasting of muscle in cancer patients
Caused by protein wasting of muscles and not being rebuilt via satellite cells
Malabsorption
Immune dysfunction
Increased glucose turnover and increased energy expenditure via tumor activity.
Cardiac muscle cells characteristics
CANNOT store energy
Always aerobic and rich in myoglobin
Utilizes primarily Fatty acids
Also uses glucose and ketone bodies produced by liver.
Lactate is more damaging to cardiac cells than skeletal cells
Why does blood flow increase in aerobic exercise?
Lactate relaxes blood vessels
