Muscle Metabolism 4e1k24

MUSCLE METABOLISM (BIOCHEMISTRY OF PHYSICAL ACTIVITY)

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TOPICS FOR DISCUSSION 1. MUSCLES- GENERAL ASPECTS AND MUSCLE TYPES 2. FUNCTIONS OF SKELETAL MUSCLE 3. GENERAL BIOCHEMICAL COMPOSITION OF SKELETAL MUSCLE 4. HIGH ENERGY MOLECULES INVOLVED IN MUSCLE CONTRACTION 5. ENERGY SOURCES FOR MUSCLE CONTRACTION UNDER NORMAL CONDITION. 6. ENERGY SOURCES FOR MUSCLE CONTRACTION DURING STARVATION/ FASTING. 7. CLINICAL ASPECTS OF MUSCLE METABOLISM 2

MUSCLE /DIFFERENT TYPES • Muscles are the contractile tissues of the body. • There are three types of muscle tissues in the body. 1.Skeletal Muscle or striated or voluntary muscle -present attached to the bone/skeleton and brings about the movements of body parts. 2.Smooth Muscle or non striated or involuntary muscle - Present in tubular internal organs such as digestive tract, trachea, blood vessels, uterus etc. 3.Cardiac Muscle -present in heart wall and also called myocardium. All types of muscle tissues are characterized by their contractility and elasticity. 3

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CARDIAC MUSCLE • • • • •

Branching cells One/two nuclei per cell Striated Involuntary Medium speed of contraction

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SMOOTH MUSCLES • • • • •

Fusiform cells One nucleus per cell Non-striated Involuntary Slow, wave-like contractions

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SKELETAL MUSCLE • • • • •

Long cylindrical cells Many nuclei per cell Striated Voluntary Rapid contractions

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FUNCTIONS OF SKELETAL MUSCLE • • • • •

Produce movement Maintain posture & body position Soft Tissues Maintain body temperature Store nutrient reserves

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BIOCHEMICAL COMPOSITION OF SKELETAL MUSCLE • Approximate Biochemical composition of the muscle tissue • Water- 75% • Proteins – 20 % • Other organic and inorganic materials – 5 % The major proteins present in muscle tissue are myosin , actin. Apart from these there are also other proteins like troponin and tropomyosin which are also important in muscle contraction. It also includes various enzymes and various transport proteins involved in muscle cell metabolism. 12

BIOCHEMICAL COMPOSITION OF SKELETAL MUSCLE The major carbohydrate present in skeletal muscle tissue is glycogen. It is an energy reserve /source. - Other organic compounds mainly include creatine – P ( also called phospho creatine) and ATP. - Creatine - P is a high energy molecule specifically involved in muscle contraction. - ATP is the immediate source of energy for muscle contraction where as creatine – P is the reserve form. - Resting skeletal muscle contains 4-6 times creatine –P than ATP. 13

HIGH ENERGY MOLECULES IN MUSCLE CONTRACTION • ATP is the immediate source of energy for muscle contraction, but its amount in the muscle is very small and is just enough for a fraction of a second.

• In human beings, ATP required for muscle contraction is formed with the help of an accessory high energy molecule called creatine – P. • Creatine – P react with ADP to form ATP and creatine. • This reaction is catalyzed by an enzyme called creatine kinase ( CK) also called creatine phospho kinase ( K). • This reaction is called Lohmann reaction. 14

HIGH ENERGYMOLECULES IN MUSCLE CONTRACTION • This reaction is reversible and creatine – P can be synthesized back from creatine and ATP during the recovery period following a muscle contraction, when ATP becomes available. • This reaction is catalyzed by another enzyme called ATP – creatine trans-phosphorylase.

• ATP can also be formed by another mechanism with the help of an enzyme called myokinase. 15

HIGH ENERGYMOLECULES IN MUSCLE CONTRACTION

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HIGH ENERGYMOLECULES IN MUSCLE CONTRACTION ATP creatine transphosphorylase ATP + CREATINE ADP+ CREATINE PHOSPHATE

CREATINE –PHOSPHATE K CREATINE + ATP

Myokinase 2 ADP

1 AMP + 1 ATP

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Turn over of creatine/creatine -P • The synthesis of creatine is taking place partially in the kidney and partially in the liver. • Creatine is synthesized from two amino acids ,namely Arginine and Glycine in a two step process. • The first /step reaction takes place in the kidney in which Arginine and glycine combines to form guanido- acetic aid. • The second step takes place in the liver during which guanidoacetate is methylated to form creatine. • Creatine is then transported to the muscle where it is phosphorylated to creatine – P ( the active form/phosphagen form). • Very negligible amount of creatine – P is dephosphorylated spontaneously and cyclised (by non-enzymatic reaction) to form creatinine ( a waste product) which is excreted in the urine.

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ENERGY SOURCE FOR SKELETAL MUSCLE • Fatty acids, D- Glucose ,amino acids and ketone bodies are the general energy sources for muscle contraction. • The type of fuel molecule utilized vary depending on the functional state of the muscle-such as resting muscle , moderate muscular activity and peak muscular activity. • And also depending on the metabolic conditionsnormal condition or starvation. 21

ENERGY SOURCE FOR SKELETAL MUSCLE 1.Resting muscle: Fatty acid are the energy source for resting skeletal muscle. -The ATP produced by fatty acid oxidation is used for the formation of creatinephosphate and glycogen ( the energy reserve). -Glycogen is synthesized from D- Glucose by a process known as glycogenesis or glycogen synthesis 22

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ENERGY SOURCE FOR SKELETAL MUSCLE 2. Moderate muscular activity: During moderate muscular exercise both glucose and fatty acids are utilised as sources of energy. a)Catabolism of D- Glucose: consists of three stages. -Glucose is oxidised by glycolysis to form pyruvate. -Pyruvate is converted to acetyl COA by Pyruvate dehydrogenase

complex ( PDC) enzyme).

-Acetyl COA is completely oxidised by the citric acid cycle in to CO2 and water. b)Catabolism of fatty acids: consists of two stages. -Fatty acids are degraded in to acetyl COA by a process called beta

oxidation.

-Acetyl COA is further degraded in to CO2 and water in the citric

acid cycle

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ENERGY SOURCE FOR SKELETAL MUSCLE 3. Peak muscular activity: Heavily exercising muscle needs more energy. There will be a high requirement of fuel molecules such as fatty acids and D- Glucose as well as molecular oxygen to the muscle tissue because of the increasing energy demand. By physiological adaptation ( high heart beat rate /increased blood circulation and high ventilation rate ), the body will try to manage this condition. But still the supply will become insufficient. 26

ENERGY SOURCE FOR SKELETAL MUSCLE In this condition the energy production will be diminished because of two reasons. 1)shortage in the supply of fuel molecule 2) insufficiency of O2. (there will be a block in aerobic mode of oxidation/mitochondria dependent oxidation which is dependent on O2 ). -The catabolism of fatty acids ( both beta oxidation and citric acid cycle) take place only in the mitochondria. -Since fatty acid oxidation is aerobic type( O2 dependent) ,the rate of fatty acid oxidation is considerably diminished in the absence of oxygen. The normal oxidation of D- Glucose also is aerobic type depending on mitochondria. Due to the lack of oxygen and insufficient supply of DGlucose ,the energy production by normal aerobic way of glucose oxidation also will be dimnished.

• In this condition mitochondria contribute only 1/3 of the ATP requirement. 27

ENERGY SOURCE FOR SKELETAL MUSCLE In short, aerobic mode of energy production from D- Glucose and fatty acid depending on mitochondria and O2 will be diminished to 30 %. In contrast, the muscle need more amounts of ATP at this time to muscle contraction process. In order to face this difficult situation muscle tissue will be forced to shift to anaerobic mode of energy production with glycogen as the fuel molecule. 28

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ENERGY SOURCE FOR SKELETAL MUSCLE:ANAEROBIC GLYCOLYSIS During heavy muscular exercise there is an increased demand for ATP. Due to the insufficient supply of O2 the aerobic mode of energy production by mitochondria will be diminished considerably (to one third of the total). In order to face this critical situation the muscle tissue will be forced to use the stored glycogen as an energy source by anaerobic mode of oxidation which is independent of the mitochondria ( takes place in the cytosol). 31

ANAEROBIC GLYCOLYSIS During heavy muscular work there will be the secretion of adrenaline ( epinephrine ) by the adrenal medulla. Adrenaline is having a stimulating effect on glycogenolysis in muscle and liver. Adrenaline will activate the chief enzyme involved in glycogenolysis,called glycogen phosphorylase. As a result of glycogenolysis glycogen will be degraded in to Glucose – 6- P . Glucose – 6- P will be further degraded in to 2 molecules of pyruvate. Pyruvate is then reduced to lactate in the cytosol itself. 32

ANAEROBIC GLYCOLYSIS • The conversion of Pyruvate in to lactate is called anaerobic glycolysis. • It takes place in the cytosol of skeletal muscle cells during heavy muscular exercise/in the absence of sufficient oxygen (and also in RBC under normal condition). • The reaction is catalyzed by an enzyme called Lactate dehydrogenase (LDH) which requires NADH+H+ as a co-enzyme. • The net energy production in anaerobic glycolysis is only 2 molecules of ATP per molecule of Glucose. 33

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ANAEROBIC GLYCOLYSIS • Reutilization of lactate: As a result of severe muscular exercise too much amounts of Lactate will be accumulated in the skeletal muscle. This in turn lead to a decrease in muscular pH resulting in a painful condition known as muscle cramp. ---This lactate is then gradually liberated in to the blood circulation. ----Via blood it reaches the liver. In the liver the lactate is effectively reutilized for the synthesis of D- Glucose by a process known as

gluconeogenesis.

The cyclic process of conversion of lactate to D-glucose(by gluconeogenesis) then to glycogen(by glycogenesis in muscle)and then to D- Glucose( by glycogenolysis in muscle)and again back to lactate ( (by anaerobic glycolysis in muscle) is known as Cori’s cycle( Cori- name of the scientist). 35

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CHANGES IN MUSCLE METABOLISM DURING FASTING AND STARVATION • During normal metabolic conditions the chief energy sources for skeletal muscles are Fatty acids ( resting state ) ,Fatty acids and DGlucose ( moderate activity) and mainly D- glucose/anaerobic glycolysis ( peak activity/severe muscular exercise). • Fasting and starvation will lead to a change in the metabolism of skeletal muscle . 38

CHANGES IN MUSCLE METABOLISM DURING FASTING AND STARVATION • During the initial hours of fasting( 9-18 hours of not consuming food )Glycogen store in the skeletal muscle will be the source of energy for muscle contraction. • By 18 hours of fasting the glycogen store of the muscle tissue will be completely utilized. • Negligible amount of D- Glucose produced by the liver as a result of gluconeogenesis will not be sufficient for the muscular activities. 39

CHANGES IN MUSCLE METABOLISM DURING FASTING AND STARVATION • During this situation there will be a change in the overall metabolism of muscle tissue in order to face the emergency situation. • The changes are: 1.The muscle tissue started utilizing ketone bodies as a source of energy. 2. Amino acids becomes a source of energy for muscle contraction. 40

Ketone body as energy source for skeletal muscle during starvation • The ketone bodies include 3 types of molecules( acetone , aceto-acetate and betahydroxybutyrate) which are produced from acetyl COA by the liver by a process known as ketogenesis. • Ketogenesis takes place in the liver at a very low rate during normal condition . • But during starvation ketogenesis will be activated. 41

Ketone body as energy source for skeletal muscle during starvation • During starvation ,there will be an increased rate of lipid mobilization( break down of neutral fat in the adipose tissue)/beta oxidation of fatty acid in the liver resulting in the accumulation of large quantities of acetyl COA in the liver. • All these acetyl COA cannot be further degraded by citric acid cycle because ,,

‘ oxalocaetate is a molecule required for the entry of acetyl COA in to the citric acid cycle. During starvation major portion of the oxaloacetate will be deviated for glluconeogenesis in the liver(under the influence of glucagon). The decrease in the concentration of oxalo acetate will limit/restrict the oxidation of acetyl COA and it will accumulate in the mitochondria excessively’. 42

Ketone body as energy source for skeletal muscle during starvation • In order to bring down/decrease the concentration of acetyl COA liver will convert the excess acetyl COA in to ketone bodies( acetone aceto-acetate and beta-hydroxy butyrate)- called ketogenesis. • Ketone bodies will be liberated in to the blood and circulated to different extrahepatic tissue. 43

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Ketone body as energy source for skeletal muscle during starvation-ketogenesis

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Ketone body as energy source for skeletal muscle during starvation-ketogenesis Major Pathway Aceto-acetyl COA + Acetyl COA HMG COA synthase Beta hydroxyl beta methyl; glutaryl COA +COASH

HMG COA lyase Aceto acetate + Acetyl COA 46

Ketone body as energy source for skeletal muscle during starvation-ketogenesis NADH beta-hydroxy butyrate dehydrogenase

4. Aceto acetate

Beta hydroxyl butyrate NAD+

5. Acetoacetate Spontaneous/ non enzymatic

CO2

Acetone (takes place in the circulation)

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Ketone body as energy source for skeletal muscle during starvation-ketolysis • Acetone will be excreted by evaporation from the body surface and also through the exhaling air( feel acetone smell). • Where as aceto-acetate and beta-hydroxy butyrate are utilized(oxidised) by certain tissues such as brain , myocardium, skeletal muscle and kidney as an energy source. This process of utilization of ketone bodies is called ketolysis.

• Ketolysis involves the enzymatic conversion of aceto acetate and beta-hydroxybutyrate in to acetyl COA. • Acetyl COA is further degraded in to CO2 and H2 0 by the citric acid cycle to liberate ATP. This ATP becomes the source of energy for muscle contraction. 48

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Ketone body as energy source for skeletal muscle during starvation-ketolysis • The heart muscle and renal cortex prefers ketone bodies over D- Glucose. • The brain and skeletal muscle use ketone bodies in the absence of sufficient quantities of D- Glucose. • This means that the absence of sufficient quantities of DGlucose enforce the skeletal muscle to use ketone bodies as an energy source during starvation.

• In this way liver helps muscle and other tissue to over come starvation by providing D- Glucose (by glycogenolysis in liver) by providing ketone bodies ( ketogenesis in liver).

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Ketone body as energy source for skeletal muscle during starvation-ketolysis • Ketogenesis- synthesis of ketone bodies. Takes plce in liver. • Ketolysis- Lysis/ oxidation / utilization of ketone bodies . Takes place in skeletal muscle , brain myocardium and kidney. • Ketonemia- excessive accumulation of ketone bodies in blood. Occurs during severe starvation and diabetes mellitus. • Ketosis- the increase in the concentration of ketone bodies all over the body tissues/accumulation of ketone bodies. • Keto-acidosis- the decrease in the pH of the blood during ketosis. • Starvation induced ketosis & diabetes induced ketosis. • Ketoneuria- the presence of more concentration of ketone bodies in urine. 51

Amino acid as an energy source for skeletal muscle during starvation Amino acids are generally the third source of energy in an individual under normal metabolic conditions after carbohydrate and fatty acids. Even though there is fat storage ( TAG in adipose tissue)and carbohydrate storage ( Glycogen in liver and skeletal muscle) as energy reserve to survive in the emergency conditions ( like starvation) , “there is no amino acid store in our body”. How ever, during severe starvation when the glycogen and fat are about to finish, the body protein( mainly muscle protein and albumin of blood plasma )will be degraded and amino acids are liberated(STARVATION INDUCED BODY PROTEIN DEGRADATION).

The liberated amino acids serve different functions. 52

Amino acid as an energy source for skeletal muscle during starvation 1. Glucogenic amino acids( 16/21) become the precursor of D- Glucose in the liver by gluconeogenesis. -D- Glucose is the only source of energy for RBCs ( NS will utilise ketone bodies during starvation, but RBCs not). 2. Ketogenic amino acids(3/21) become the precursor of ketone bodies- the energy source for skeletal muscle , myocardium, kidney and brain during starvation.

3. Amino acids are de- aminated ( by different mechanisms) and the carbon skeletons are oxidised by the citric acid cycle to produce energy for muscle contraction. 53

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Clinical aspects of muscle metabolism 1.Muscle Fatigue – When muscles can no longer perform a required activity, it is said to be fatigued.

Characteristics of Muscle Fatigue – Depletion of metabolic reserves – Damage to sarcolemma and sarcoplasmic reticulum

– Low pH (lactic acid) – Muscle exhaustion and pain 56

Clinical aspects of muscle metabolism 2. Muscle cramp- muscle pain experienced during /after sever muscular exercise . -This is because of the accumulation of lactic acid ( formed during anaerobic glycolysis)and a decrease in muscle p H. 3. Duchnee muscular distrophy is a genetic disorder ( progressive type)characterised by muscle deterioration and non functioning of the muscle. It is because of the degeneration/atrophy / death of myocytes. This usually happens to muscles of pelvic and shoulder girdle. 57

Clinical aspects of muscle metabolism 4. Malignant hyper thermia: a serious complication arise during certain type of anaesthesia due to the accumulation of Ca ++ ions in the cytosol of the skeletal myocytescausing rigor and generation of excessive heat. 5.Mc Ardle’s disease: is a muscular disorder characterised by muscle weakness during exercise- known as exercise intolerance. This is because of the genetic deficiency of an enzyme called muscle glycogen phosphorylase which is involved in muscle glycogenolysis ( glycogen breakdown). Anaerobic mode of energy production will be blocked in this condition because of a block in muscle glycogenolysis.

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Muscle mass enlargement: muscle hypertrophy • Muscle hypertrophy involves an increase in size of skeletal muscle through a growth in size of its component cells. • Two factors contribute to hypertrophy: 1)Sarcoplasmic hypertrophy, which focuses more on increased muscle glycogen storage & 2)Myofibrillarhypertrophy, which focuses more on increased myofibril size. • However, neither happens in isolation, which is why top-level bodybuilders and strongman competitors differ so greatly in muscle size and strength. 59

Muscle mass enlargement: muscle hypertrophy • In the bodybuilding and fitness community skeletal muscle hypertrophy is described as being in one of two types: Sarcoplasmic or myofibrillar. • During sarcoplasmic hypertrophy, the volume of sarcoplasmic fluid in the muscle cell increases with no accompanying increase in muscular strength. During myofibrillar hypertrophy contractile proteins(actin and myosin increase in number and add to muscular strength as well as a small increase in the size of the muscle. 60

Muscle mass enlargement: muscle hypertrophy • Sarcoplasmic hypertrophy is greater in the muscles of bodybuilders while myofibrillar hypertrophy is more dominant in Olympic weightlifters. • These two forms of adaptations rarely occur completely independently of one another; one can experience a large increase in fluid with a slight increase in proteins, a large increase in proteins with a small increase in fluid, or a relatively balanced combination of the two. 61

AT THE END ONE FUNNY QUESTION PLEASE,,,,,,,,,,,,,,

WHO IS HAVING MORE MUSCLE SIZE AND STRENGTH??????MALES OR FEMALES. 62

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