Muscle Metabolism Lecture Notes PDF, Spring 2024

BMS 201 Lecture No: Title: Muscle Metabolism Instructor Name: Dr Wael Elayat Medicine and Surgery Program Spring 2024  ILOs By the end of this lecture, you should be able to: 1- Identify that muscle uses 3 energy syste...

BMS 201 Lecture No: Title: Muscle Metabolism Instructor Name: Dr Wael Elayat Medicine and Surgery Program Spring 2024  ILOs By the end of this lecture, you should be able to: 1- Identify that muscle uses 3 energy systems. 2- Describe creatine-phosphate energy system 3- Describe synthesis of creatine, creatine-phosphate 4- Describe creatinine, degradation product of creatine and its clinical significance. 5- Recognize CK and its isozymes and their clinical significance. 6- Describe glycogen 7-Realize the need of muscle for glycogen. 8- Describe steps of glycogen synthesis 9- Describe steps of glycogen breakdown 10- Explain regulation of glycogen metabolism: allosteric & hormonal 11- Relate enzymatic defects in glycogen metabolism to metabolic diseases The primary fuel used to support muscle contraction depends on: 1. Magnitude and duration of exercise 2. The major fibers involved. Skeletal muscle has stores of both glycogen and some triglycerides. Blood glucose and free fatty acids may be also used.  Types of muscle fibers Type II, fast fibers, Type I, slow fibers, glycolytic, white oxidative, red fibers fibers) Predominantly Active in aerobic active in anaerobic conditions. conditions. Muscle contraction and, therefore, all exercise are dependent on the breakdown of ATP and the concomitant release of free energy. This free energy release is coupled to the energy requirements for muscle contraction. ATP → ADP + Pi + energy −→ muscle contraction  The total quantity of ATP stored within the cells of the body is very small (approximately 8 mmol/kg wet weight of muscle) which is sufficient for contraction for maximum 4 seconds.  Thus, muscle rely on replenish ATP store. Memorize your self - Muscle is a biochemical ………… - The primary fuel support for muscle contraction depend on: 1-…………. 2- ……………. - ATP store is sufficient for activity for hours (x)/(√) - Muscle relay on ………….. ATP for its activity  ATP stores ATP stores in Then, anaerobic The anaerobic muscle are glycolysis from blood pathway occurs in depleted during the glucose or mostly from the cytosol first 4 seconds of catabolism of muscle exercise. glycogen which provides while ATP is regenerated ATP for 1-2 minutes. the aerobic pathway by direct occurs in the In prolonged exercise mitochondria. phosphorylation which lasts for hours, with creatine ATP is regenerated using phosphate. aerobic pathway which This phase lasts for uses free fatty acids and 10 seconds. glucose as fuels. Mechanisms for replenish store of ATP in muscle 1- ATP phosphocreatine system (the Phosphagen, direct phosphorylation, anaerobic). 2- The Glycolytic System (glycogen/lactate system, anaerobic). 3- Oxidative phosphorylation (fatty acid, aerobic glycolysis) 1- ATP phosphocreatine system Creatine kinase Creatine phosphate +ADP+H+ ATP+ Creatine In class assessment - Which of the following is a fuel source of energy in absence of oxygen a) Fatty acids b) Ketone bodies c) Creatine d) Glycogen or glucose 1- Phosphocreatine system Metabolism of creatine phosphate A- Anabolism (Synthesis) - Creatine phosphate is found in muscle: - It is a high energy compound which maintain intracellular level of ATP (in the first few seconds) during intense muscle exercise. This system dominates in first few seconds of intense muscular contraction such as the 100 m dash or lifting weights.  1- Phosphocreatine system Metabolism of creatine phosphate A- Anabolism (Synthesis) - Creatine phosphate is a high energy compound, found in muscle. i- Site of synthesis: - It start its synthesis in the kidney, then continue in the liver and end in the muscle (where it stored). - So synthesis of creatine phosphate depend mainly on healthy functioning kidney and liver - The amount of creatine phosphate depend on muscle mass. ii- Requirement for its synthesis: Creatine phosphate is synthesized from 3 amino acids: - Glycine , Argnine (guanido group of argnine) and methionine (as a donor of methyl group)  After creatine is synthesized in the liver, it diffuse to blood. Creatine taken up and stored by: a) Skeletal muscle b) Heart c) Brain Creatine : - Reversibly phosphorylated in such organs and remain as such for maintaince of cellular ATP level in time of need, by phosphorylating ADP to form ATP In class assessment 1- Synthesis of creatin start in a) Liver b)Muscle c) Brain d) kidney e) Heart 2- Which of the following amino acids is required for creatine synthesis a) Tyrosine b)Active methionine c) Alanine d) Glutamic acid e) Cystine  B- Fate of creatine Creatinine is constantly synthesized daily from breakdown of creatine and creatine phosphate. Creatinine diffuse out from muscle to blood where it is excreted from kidney (by filtration and active excretion) in urine. The creatinine level in urine in normal individual is constant. 1- Creatinine level in blood and urine 2- As creatinine is constantly is directly proportionate to total synthesizes, and as it is only excreted content of creatine phosphate in by the kidney, estimation of plasma the body, which is correlated to creatinine level could be used as an muscle mass. Level of creatinine indicator of kidney function. can be used as indicative of muscle mass. Elevation of creatinine level in plasma indicate impaired kidney function.   3- The level of creatinine decrease in 4- CK has three isoenzymes: blood and urine in any condition of muscle CK-MM (mainly in skeletal dystrophy (as paralysis or muscle atrophy). muscle), CK-MB (mainly in heart muscle) and  Normal serum creatinine: 0.6 to 1.2 mg/ dL CK-BB (mainly in brain). in adult males and 0.5 to 1.1 mg/dL in adult females. Serum total CK is increased in cases with damage of skeletal or cardiac muscles (myocardial infarction)  2- Glycolytic system of ATP synthesis a- Glycogen Metabolism I- Glycogenesis i-Def.: Synthesis of glycogen to store excess glucose in less space. -Actually glycogenesis is an elongation to a glycogen primer. ii-Site: the process of glycogenesis occur in cytoplasm of liver and muscle.  I- Glycogenesis 1- Preparation of a substrates which are: cont., i- Glycogen primer ii- UDP glucose iii-Steps: a- Glycogen primer: Glycogenesis starts - What is the glycogen primer? by: It is a stretch of 4-6 molecules of glucose residues linked together by α 1,4 glycosidic linkage. - Why glycogen primer must be 1- Preparation of a synthesized? substrate. As the glycogen synthase (enzyme responsible for synthesis of glycogen) can 2- Elongation of not initiate chain synthesis using glucose as glycogen chain. an acceptor of other molecule of glucose from UDP glucose. I- Glycogenesis steps cont., - A fragment of stored glycogen can act as a glycogen primer but if glycogen depleted, glycogenin protein can act as glycogen primer. - How new glycogen primer synthesized (if glycogen depleted)? Glycogenin act as glucosyl transferase and auto glucosylate itself, then it catalyze transfer of glucose from UDP glucose forming short linked glucosyl chain which will act as a primer for glycogen synthesis. b- Synthesis of UDP glucose: 1- Glucose first converted to glucose 6 phosphate by hexokinase (in muscle) or glucokinase (in liver). 2- Then by phosphoglucomutase enzyme, glucose 6 phosphate converted to glucose 1 phosphate. 3- Glucose 1 phosphate react with UTP under effect of UDP-glucose pyrophosphorylase (also known as glucose 1 phosphate uridyl transferase) enzyme producing UDP-glucose and pyrophosphate (P~P).  I- Glycogenesis steps cont., 2- Elongation of glycogen chain Elongation of glycogen chain (or glycogen primer) occurs under influence of glycogen synthase and branching enzymes. - Glycogen synthase catalyze formation of 1,4 iv- Importance (significance): glycosidic bond by transfer glucose from UDP-glucose to the glycogen primer. 1- Synthesis of glycogen to maintain blood glucose level in early - Branching enzyme: starvation. Catalyze transfer of 4-6 molecules of glucose in block from 1,4 to 1,6 glycosidic bond (1,4- 2- Store excess glucose in less 1,6 glucosyl transferase activity), and so space by decreasing osmotic effect establish a branch point. of glucose.  II- Glycogenolysis Steps:  In muscle In the liver Due to absence of glucose 6 Due to presence of glucose 6 phosphatase enzyme, the phosphatase enzyme, glucose 6 process of glycogenolysis end phosphate converted to free by glucose 6 phosphate, which glucose to maintain blood glucose utilized to supply energy level during early starvation. needed for muscle contraction. 27 Regulation of glycogen metabolism A- Regulation of glycogenesis Regulation of glycogen metabolism A- Regulation of glycogenesis i- Hormonal regulation -The key regulatory enzyme of glycogenesis is glycogen synthase. ii- Allosteric regulation 1- Glucose 6 - This enzyme is present in 2 forms: phosphate and ATP 1- Glycogen synthase I (or a or active or dephosphorylated form). allosterically activate 2- Glycogen synthase D (or b or inactive or phosphorylated form). glycogen synthase a and so activate glycogenesis. - The glycogen synthase is covalently activated by insulin as it is active in dephosphorylated form. 2- Glycogen and ADP as well as AMP allosterically inhibit - The glycogen synthase is covalently inhibited by glucagon (in glycogen synthase a liver only) and epinephrine (in liver and muscle) as it is inactive in and so inhibit glycogenesis. phosphorylated form. Regulation of glycogen metabolism B- Regulation of glycogenolysis  Regulation of glycogen metabolism B- Regulation of glycogenolysis i- Hormonal regulation - The key regulatory enzyme of glycogenolysis is glycogen phosphorylase. ii- Allosteric regulation - This enzyme is present in 2 forms: 1- Glucose 6 phosphate and ATP a- Active phosphorylated form (or a form) allosterically inhibit glycogen b- Inactive dephosphorylated form (b form) phosphorylase a and so inhibit glycogenolysis. - The glycogen phosphoryliase is covalently inhibited by insulin as it is inactive in 2- Increase intracellular Ca, lead to binding of Ca to calmodulin forming dephosphorylated form. Ca-calmodulin complex. Ca-calmodulin complex allosterically activate phosphorylase kinase, - The glycogen phosphorylase is covalently which in turn activate glycogen activated by glucagon (in liver only) and phosphorylase. epinephrine (in liver and muscle) as it is active in phosphorylated form.  Inborn error of glycogen metabolism Glycogenosis (Glycogen storage diseases) These are a group of inborn error of metabolism which affect glycogen metabolism. Types of glycogen storage diseases: Type Name of disease Name of deficient enzyme Clinical picture I Von Gierck`s Deficiency of glucose 6 phosphatase - Fasting hypoglycemia disease - Hepatomegaly with increase hepatic content of glycogen and TAG II Pomp` disease Deficiency of lysosomal acid maltase Lethal with early death III Cori disease Deficiency of debranching enzyme Myopathy IV Anderson disease Deficiency of branching enzyme Failure to thrive V Mac Ardle disease Deficiency of muscle glycogen Myopathy phosphorylase VI Hers` disease Deficiency of hepatic glycogen - Fasting hypoglycemia phosphorylase - Hepatomegaly with increase hepatic content of glycogen and TAG  References: - Lippincott Illustrated Review Integrated system - Lippincott Illustrated Review 6th edition - Oxford Hand book of Medical Science 2nd edition - Clinical Key Student THANK YOU