MUSCLE BIOCHEMISTRY

2017
 Learning Objectives

At the end of the session students will be able to:

• Define what is muscle
• Describe about muscle metabolism
• Explain about energy sours of for muscle metabolism
• Discuss muscle glycogenesis, glycogenolysis, and
anaerobic glycolysis
• Discuss manifestation of muscle cramp, lactate
reutilization and biochemistry of synovial fluid
Muscle
• is the fleshy organ of the body that converts
potential energy of food into mechanical
energy.
• Muscle cells have a special capacity to utilize
chemical energy
– to produce force and movement
– to produce speech and
– to manipulate objects around us
 Types of Muscles
Three types
1.Skeletal/voluntary muscles
 Located attached to bones & moves skeleton
 They are elongated, cylindrical and
multinucleated cells,
 They are striated muscle
 They are voluntary muscle, controlled by
somatic N.S
2. Cardiac muscle:
– muscle of the heart
– They are striated
– They are involuntary, controlled by ANS, drugs and
hormones
– Have the property of autorhythmicity and syncytium
3. Smooth muscles
– Located in the wall of hallow organs (GIT, blood vessels,
uterus, u-bladder, Iris)
– They have non-striated appearance, mononucleated cells
– Involuntary muscle, controlled by ANS, drugs and
hormones
Types of muscles
 Muscle Metabolism
 The chemical energy released by the hydrolysis of
ATP is necessary for both
muscle contraction and
muscle relaxation.
 Muscles typically store limited amounts of ATP –
enough to power 4-6sec. of activity.
So resting muscles must have energy stored in
other ways.
 Resting muscle fibers typically takes up fatty acids from the
blood stream.
– Inside the muscle fiber, the fatty acids are oxidized to
several molecules of a compound called Acetyl-CoA.
– Acetyl-CoA will then enter a cyclical series of reactions
known as the Krebs cycle or Tricarboxylic Acid cycle.
– In the Krebs cycle, acetyl-CoA combines with the
compound oxaloacetate and then enters a series of rxns.

– The end product of these rxns is CO2, ATP, NADH,

 Oxaloacetate will simply combine with another molecule of
acetyl-CoA and reenter the cycle
• NADH and FADH will enter another series of rxns known as
the Electron Transport Chain.
• These rxns occur in the mitochondrion and they used to drive
the synthesis of ATP.
• CO2 will diffuse out of the mitochondria, out of the muscle
fiber, and into to the blood stream which will take it to the
lungs.
• The ATP made in the Krebs cycle plus the ATP made during
the Electron Transport Chain will be used in many ways.
 ATP Use in the Resting Muscle Cell
• ATP is necessary for cellular housekeeping
/basic cellular/duties.
• ATP used to convert glucose in to stored
glycogen.
• ATP is used to create another energy storage
compound called creatine phosphate or
phosphocreatine:
ATP + Creatine  ADP + Creatine-Phosphate
by action of the enzyme creatine kinase
 Working Muscle
• When a muscle contracts against a load, it performs work.
• This means that energy is transferred from the muscle to
the external load to lift an object to a greater height.
• In mathematical terms, work is defined by the following
equation: W = L x D
W = work output,
L = load, and
D = the distance of movement against the load.
• The energy required to perform the work is derived from
the chemical reactions in the muscle cells during
contraction.
Cont’d
 The energy metabolism of skeletal muscle is unique respond
to muscle contraction.
 At rest, muscle accounts for approximately 30% of the
oxygen consumption of the body
 At vigorous exercise, it is responsible for up to 90% of the
total oxygen consumption
Cont’d
 Major fuels are glucose, fatty acids, and ketone bodies
– -> Has a storage of glycogen -> about ¾ of all glycogen
stored in muscles
– -> Glucose is preferred fuel for burst of activity ->
production of lactate
– -> Fatty acid major fuel in resting muscles and in heart
muscle (aerobe)
Heart muscle differs skeletal muscle in three important
ways:
 The heart -continuously active, but skeletal muscle
 The heart -completely aerobic metabolism; and
 The heart - no energy stores, such as glycogen or lipid.
Metabolic Profile of Muscles

Glucose
Glucose ATP used for gluconeogenesis
during recovery

ATP
ATP

ATP produced by glycolysis is for rapid

contraction
Cont’d
 Skeletal Muscle in Fasting

Resting muscle uses fatty acids as its major fuel source.

 While exercising muscle initially uses its glycogen stores

 During intense exercise, glucose 6-phosphate derived from glycogen

is converted to lactate by anaerobic glycolysis .

 As these glycogen reserves are depleted, free fatty acids

provided by the mobilization of TAG from adipose tissue

become the dominant energy source .

 Glycolysis
 It is an oxidation of glucose to give pyruvate or lactate

 It takes place in the cytoplasm of all tissue cells, but it is

importance in:
1. Tissues no mitochondria: mature RBCs, cornea & lens
2. Tissues with few mitochondria: Testis, leucocytes, medulla of
the kidney, retina, skin and GIT
3. Tissues undergo frequent oxygen lack: skeletal muscles
especially during exercise.
 Glycolysis
glucose Glycolysis
ATP
Hexokinase
ADP
glucose-6-phosphate
Phosphoglucose Isomerase
fructose-6-phosphate
ATP
Phosphofructokinase
ADP
fructose-1,6-bisphosphate
Aldolase

glyceraldehyde-3-phosphate + dihydroxyacetone-phosphate
Triosephosphate
Isomerase
Glycolysis continued
 Glycolysis cont’d

glyceraldehyde-3-phosphate
NAD+ + Pi Glyceraldehyde-3-phosphate
NADH + H + Dehydrogenase
1,3-bisphosphoglycerate
ADP
Phosphoglycerate Kinase
ATP
3-phosphoglycerate
Phosphoglycerate Mutase
2-phosphoglycerate

H2O Enolase
phosphoenolpyruvate
ADP
Pyruvate Kinase
ATP
pyruvate
 Bioenergetics of glycolysis
Under anaerobic conditions:
 ATP invested in the activation phase

 One ATP in the activation of glucose to Glu-6-P.

 One ATP in the activation of F-6-P to F-1,6-DiP.

 Total ATP invested = 2 ATP

 ATP Gained:

 2 ATP by substrate level phosphorylation from 1,3-

diphosphoglycerate.
Cont’d
 2 ATP from substrate level phosphorylation from PEP.

Net ATP gained = 4 ATP gained - 2 ATP lost = 2 ATP for

glucose into lactate.
 During rapid contraction, muscle cells require a very fast
supply of energy in the form of ATP.
 The extra demand of ATP is met by glycolysis because
substrate level phosphorylation is 100-times faster than
oxidative phosphorylation
 Under aerobic conditions

 Total ATP invested in the activation phase = 2 ATP,

as under anaerobic conditions.
 Total ATP gained = 8

A. 4 ATP (obtained by substrate level phosphorylation)

B. 2 NADH.H+ (produced from oxidation of

glyceraldehyde-3-phosphate);
Cont’d
1 NADH.H+ can give rise to either two or three ATP
through respiratory chain depending upon which
shuttle system is used for its transfer across the
mitochondrial membrane;
• Therefore, 2X3 ATP/ 2ATP = 6 ATP/ 4ATP.

• Net ATP gained : 6ATP+2 ATP = 8 ATP / 6ATP

 Fates of pyruvate

1. Entry into the citric acid/ TCA cycle.

 Glycolysis releases relatively little of the energy present in a
glucose molecule;
 much more is released by the subsequent operation of the
TCA cycle and oxidative phosphorylation
 Following this route under aerobic conditions, pyruvate is
converted to acetyl CoA by the enzyme pyruvate
dehydrogenase and the acetyl CoA then enters the TCA
cycle.
2. Conversion to FAs or Ketone Bodies

When the cellular energy level is high (ATP in

excess), the rate of the TCA cycle decreases
and acetyl CoA begins to accumulate.
 Under these conditions, acetyl CoA can be
used for FA synthesis or the synthesis of
ketone bodies
 3. Conversion to Lactate
 The NAD+ used during glycolysis (in the formation of 1,3-
bisphosphoglycerate by glyceraldehyde 3-phosphate
dehydrogenase; must be regenerated if glycolysis is to
continue.
 Under aerobic conditions, NAD+ is regenerated by the
reoxidation of NADH via the electron transport chain
 When oxygen is limiting, as in muscle during vigorous
contraction, the reoxidation of NADH to NAD+ by the
electron transport chain becomes insufficient to maintain
glycolysis.
 Under these conditions, NAD+ is regenerated instead by
conversion of the pyruvate to lactate by lactate dehydrogenase
Cont’d
 Fate of Lactate

 When sufficient oxygen becomes available once more, NAD+ levels rise
through operation of the electron transport chain.
 The lactate dehydrogenase reaction then reverses to regenerate pyruvate that is
converted by pyruvate dehydrogenase to acetyl CoA which can enter the TCA
cycle
 Lactate dehydrogenase in mammals oxidize NADH to NAD+ hence produced
ATP under anaerobic conditions.
 Lactate produced in contracting skeletal muscle is transported in the
bloodstream
 Then to the liver where it is converted back to glucose and can return once
again via the bloodstream to the skeletal muscle to be metabolized to yield
energy
Cont’d
Reduction of pyruvate to lactate:
 Lactate formed by the action of lactate dehydrogenase, is the
final product of anaerobic glycolysis in eukaryotic cells.
 The formation of lactate is the major fate for pyruvate in lens
and cornea of the eye, kidney medulla, testes, leukocytes and
red blood cells.
 because these are all poorly vascularized and/or lack
mitochondria.
 Lactate formation in muscle:

 In exercising skeletal muscle, NADH production by

glyceraldehyde 3-phosphate dehydrogenase and by the three
NAD+-linked dehydrogenases of the citric acid cycle, exceeds the
oxidative capacity of the respiratory chain.
 This results in an elevated NADH/NAD+ ratio, favoring reduction
of pyruvate to lactate.
 Therefore, during intense exercise, lactate accumulates in muscle,
causing a drop in the intra cellular pH, potentially resulting in
muscle cramps.
 Much of this lactate eventually diffuses into the bloodstream, and
can be used by the liver to make glucose.
 Lactate consumption:

 The direction of the lactate dehydrogenase reaction depends on

 The relative intracellular concentrations of pyruvate and lactate,
and
 The ratio of NADH/NAD+ in the cell.

For example: in liver and heart, the ratio of NADH/NAD+ is lower

than in exercising muscle.
 These tissues oxidize lactate obtained from the blood to pyruvate.
 In the liver, pyruvate is either converted to glucose by
gluconeogenesis or oxidized in the TCA cycle.
 Heart muscle exclusively oxidizes lactate to CO2 and H2O via the
THE CORI &GLUCOSE - ALANINE
CYCLE
 Conversion to Ethanol

 In yeast and some other microorganisms under anaerobic

conditions,
 The NAD+ required for the continuation of glycolysis is
regenerated by a process called alcoholic fermentation.
 The pyruvate is converted to acetaldehyde (by pyruvate
decarboxylase) and then to ethanol (by alcohol
dehydrogenase)
 GLYCOGEN METABOLISM

 Storing CHOs is essential for eukaryotes particularly in the

form of glycogen due to the following advantages:
 Dietary intake of glucose and glucose precursors is sporadic.

 Storage of glucose in the form of fat is not suitable because:

1. Fat cannot be mobilized as rapidly in muscles as glycogen.

2. Fat cannot be used as a source of energy in the absence of

O2 as glucose
Cont’d
3. Unlike glycogen, fat cannot be transformed directly to
glucose by any pathway in human body to guarantee blood
glucose levels for tissues critically requiring glucose, e.g., RBCs
and Brain tissue
 Glucose cannot be stored as such within the cells because it is
osmotically active and at equivalent amounts to glycogen
 It will induce osmotic lysis of the cell due to the uptake of
considerable amounts of water
Cont’d
Tissue Normal tissue Glycogen stores
mass

Liver 1800 g 75 - 180 g

Skeletal muscles 35 kg 100 - 300 g
Extra-cellular 10 liter 10 g
glucose

Total 185 - 490 g

 Synthesis of Glycogen (Glycogenesis)

 Glycogenesis takes place in the cytoplasm of almost all tissues of the body

 The turnover of glycogen in liver and skeletal muscles is rapid and

significant
 Muscle glycogen serves as emergency store for its own usage during
exercise
 While the liver glycogen serves to maintain blood glucose level during
fasting
 Synthesis of glycogen from Glucose is carried out by the enzyme
Glycogen Synthase.
Cont’d
 The activation of glucose to be used for glycogen synthesis is carried out

by the enzyme UDP-glucose pyrophosphorylase.

 The energy of the phosphoglycosyl bond of UDP glucose is utilized by

glycogen Synthase to catalyze the incorporation of glucose in to

Glycogen.

 Glycogen synthase is not able to synthesize glycogen de novo.

 It can only extend the already existing glycogen, glycogenin primer

molecule by adding glucose units at its non-reducing C4 end

Cont’d

Fig Glycogen synthesis

 Glycogen Catabolism (Glycogenolysis)

 Glycogen Phosphorylase catalyzes phosphorolytic cleavage

of the α(14) glycosidic linkages of glycogen, releasing
glucose-1-phosphate
 α-1,4 glycosidic link is cleaved by phosphorylysis with
retention of energy potential in the phosphate ester of glucose-
1-phosphate.
 It stops at fourth glucose from α-1,6 branch point

 It is activated by phosphorylation, regulated by glucagon and

epinephrine
Cont’d
Cont’d

Fig :Allosteric regulation of glycogen

synthesis and degradation. A. Liver.
B. Muscle. [Note: Ca2+ indirectly
activates phosphorylase in both
muscle and liver by directly
activating phosphorylase kinase.]
 Muscle Cramps

 Muscle cramps manifest as sudden, involuntary, and painful

contractions or spasms in a muscle.
 accompanied by a feeling of tightness or a bulging lump
beneath the skin, and
 can last from seconds to minutes.
 General Symptoms

 Sudden, involuntary muscle contraction or spasm: This is the

hallmark of a muscle cramp.
 Pain: The pain can range from mild discomfort to intense, sharp pain.

 Muscle tightness or stiffness: The affected muscle may feel hard or

tense to the touch
 Bulging lump: You might notice a visible lump beneath the skin
where the cramp is occurring.
 Muscle twitching: In some cases, you might see the muscle twitching
or moving uncontrollably.
Cont’d
 Post-cramp soreness: After the cramp subsides, the affected area
might feel sore for a few hours or even days.
 Impaired function: Cramps can make it difficult to walk, move, or
perform other activities.

Specific Locations:
 Leg cramps: These are very common, often affecting the calf
muscles, but can also occur in the thigh or foot.
 Other locations: Cramps can also occur in the hands, arms,
chest, belly, back, or feet.
 Synovial fluid
 Synovial fluid, is a fluid which is found in joint
cavities.
 It is protein-rich ultrafiltrate of plasma.

 It lubricates and nourishes joints.

 It containing hyaluronic acid for viscosity and

other components like lubricin and
proteoglycans.
Key Components and Functions
Hyaluronic Acid (HA):
• A major component that provides the fluid's characteristic viscosity and
lubricating properties.

Lubricin:
• A protein that acts as a primary lubricant for boundary lubrication,
reducing friction between joint surfaces.

Proteoglycans:
• These molecules, along with HA, contribute to the fluid's viscosity and
ability to absorb shock.
Cont’d
Other Proteins:
• Synovial fluid contains various proteins, including those derived from
plasma and those produced by synoviocytes (fibroblast-like cells) within
the joint tissues.
Small Molecules:
• Electrolytes, glucose, and other small molecules are present in
concentrations similar to those in plasma.
Enzymes:
• Synovial fluid contains enzymes like matrix metallopeptidase 1 (MMP-1),
elastase, and plasmin, which play roles in joint health and disease
 Origin and Production
 Synovial fluid is produced as an ultrafiltrate of blood plasma,
and modified by the synovial membrane.
 The synovial membrane, a tissue lining the joint, plays a
crucial role in regulating the volume and composition of the
fluid.
 Synoviocytes, specialized cells within the synovial membrane,
secrete hyaluronic acid and other components that contribute
to the fluid's properties.
 Functions of synovial fluid
 Lubrication: Synovial fluid reduces friction between the joint
surfaces, allowing for smooth and painless movement.
 Nutrition: It provides nutrients to the avascular cartilage and
other joint tissues.
 Shock Absorption: The fluid helps to absorb mechanical
stress and impact on the joint.
 Inflammation Modulation: Synovial fluid plays a role in
regulating inflammation within the joint.
 Clinical Significance:
 Analysis of synovial fluid can help in diagnosing various joint
disorders, including: Arthritis, Gout, and Infections.
 Changes in the color, clarity, viscosity, and composition of
synovial fluid can provide insights into the health and disease of
the joint.
 For example, increased levels of certain proteins or enzymes in
synovial fluid can indicate inflammation or damage to the joint
tissues.
 Biochemical markers in synovial fluid can also identify early
osteoarthritis.