Muscle Contraction and Energy Metabolism

1. Muscle Contraction and Energy Metabolism Prof. Dr. Serdar Öztezcan Medical Biochemistry

2. Contents • structure of muscles • mechanism of contraction • energy metabolism for contraction • similarities and differences in muscles • clinical correlations

3. Introduction • The largest single tissue • 25% of total body mass in newborn • more than 40% in the young adult • less than 30% in the aged adult

4. Introduction • Three types of muscle • skeletal • cardiac • smooth

5. Introduction • Their common function is the conversion of chemical energy to mechanical energy • They differ • mechanism of initiation of contraction • rate of force development • duration of contraction • substrate utilization • innervation • contractile protein arrangement • propagation of depolarization

6. Introduction • Muscle activity is a major determinant of the overall metabolic rate in both the basal and active state • Loss of muscle mass has a profound effect on overall metabolism • Advancing age and wasting diseases are conditions associated with loss of muscle mass • This loss is associated with increased morbidity and mortality

7. Introduction • Skeletal muscle • locomotion • a source of body heat • provides amino acids for hepatic gluconeogenesis • major site of glucose and triglyceride disposal

8. Structure • A common characteristic of cardiac myocytes, smooth muscle cells and skeletal myofibers is that their cytoplasm is packed full of contractile protein • The contractile protein is arranged in linear arrays of sarcomere units in skeletal myofibers and cardiac myocytes..... striated muscle • Contractile protein in smooth muscle cells is not organized into a sarcomeric structure ....... nonstriated muscle

9. Structure • Skeletal muscle consists of bundles (fasciculi) of elongated, multinucleated fiber cells(myofibers) • surrounded by an excitable plasma membrane sarcolemma • Fiber cell contains a bundle of many myofibrils • embedded in intracellular fluid termed sarcoplasm • Myofibrils are composed of thick and thin myofilament proteins • the thick filament ...... myosin • the thin filament ....... actin, tropomyosin and troponins • form the sarcomere

11. Structure (Summary) • Microscopic unit, • fasciculus: bundle of muscle cells • Cellular unit, • myofiber: long, multinucleated cell • Subcellular unit • myofibril: composed of myofilament (thick, thin) proteins • Myofilament components • proteins; primarily myosin and actin • Functional unit • sarcomere: repeating unit of the myofibril

12. Sarcomere • Electron microscopic analysis of myofibril reveals a repeating pattern of light- and dark-staining regions • These regions are known as the I (isotropic)- and A (anisotropic)-bands, respectively • At the center of the I-band is a discrete, darker staining Z-line • the center of the A-band has a lighter staining H-zone with a central M-line • The sarcomere is centered on the M-line, extending from one Z-line to the next • The M-and Z-lines are base plates for anchoring the filaments

15. Sarcomere proteins;Myosin • one of the largest proteins in the body • accounts for more than half of muscle protein • primary component of the thick filament • made of two heavy chains and four light chains • heavy chain can be subdivided into the helical tail and globular head regions • light chains are bound to the globular heads • two flexible hinge regions • myosin filaments are associated through their helical regions and extend outward from the M-linetoward the Z-line

17. Myosin

18. Myosin • There are several features of myosin that are essential for muscle contraction • Myosin binds reversibly actin to form actomyosin (actin-myosin) • globular heads have binding sites for ATP and its hydrolysis products, ADP and phosphate (Pi) • globular heads have a Ca2+-dependent ATPase activity

19. Sarcomere proteins:Actin • composed of G-actin (globular), which polymerize into a filamentous array (F-actin) • Two polymer chains coil around one another to form the F-actin myofilament • F-actin is the major component of the thin filament and interacts with myosin in the actomyosin complex • The F-actin chains extend in opposite directions from the Z-line, overlapping with the myosin

20. Actin

21. Sarcomere proteins:Tropomyosin and Troponins • Tropomyosin is a fibrous protein that extends along the grooves of F-actin • The troponin complex is bound to tropomyosin: • Tn-T (tropomyosin-binding) • Tn-C (calcium-binding) • Tn-I (inhibitory)

22. Tropomyosin and Troponins

23. Myosin / Actin

24. Clinical correlation:Myocardial Infarction • The cardiac troponins differ slightly from those in skeletal muscle • Specificity in clinical diagnostic test for Myocardial Infarctus

25. THE CONTRACTILE PROCESS The sliding filament model • Based on morphologic observation on resting and contracting muscle • When muscle contracts, there is no change in lengths of the thick and thin filament, but sarcomere, H zone and the I bands shorten

26. THE CONTRACTILE PROCESS The sliding filament model

27. The sliding filament model • In resting, relaxed muscle (1) • calcium concentration is 10-7 mol/L • head of myosin contains bound ADP and Pi • head of myosin is extended from the axis of helix(90o cocked state ) in a high-energy conformation • Although the myosin-ADP-Pi complex has a high affinity for actin, binding of myosin to actin is inhibited by tropomyosin, which blocks the myosin-binding site on actin at low calcium concentration

30. the sliding filament model (cont) • When muscle is stimulated (2) • calcium enters the sarcoplasm through voltage-gated calcium channels • calcium binding to Tn-C causes a conformational change in Tn-I, which is transmitted through Tn-T to tropomyosin • movement of tropomyosin exposes the myosin-binding site on actin • Myosin-ADP-Pi binds to actin, forming a“cross-bridge”

33. the sliding filament model (cont.) • power stroke (3) • release of Pi, then ADP from myosin during the interaction with actin is accompanied by a major conformational change in the hinge regionsof myosin • snap back to their original 45oangle with the tails, producing the 'power stroke‘ • moves theattached actin towards M bond • increases their overlap and causing muscle contraction • myosin is now in low-energy state (No ADP- ATP)

35. the sliding filament model (cont.) • preperation to next (4) • Ca2+ pumped back into sarcoplasmic reticulum by Ca2+-ATPase and Na+/ Ca2+-antiporter • Release of Ca2+ from troponin • binding of ATP to myosin leads to dissociation of the cross-bridge • hydrolysis of ATP restore the high-energy conformation, setting the stage for continued muscle contraction

38. Rigor Mortis • The increase in Ca2+ in the sarcoplasm and decrease in ATP after death lead to tight binding between myosin and actin, forming rigid muscle tissue

40. Muscle membrane depolarization : Skeletal muscle • Stimulus leads to depolarization of the electrochemical gradient across the sarcolemma • caused by influx of Na+ • propagates rapidly along the sarcolemma • is transmitted into the muscle fiber by invaginations of the plasma membrane, called transverse tubules (T tubule), • signals a voltage-gated calcium channels • leads to rapid, concerted release of calcium from the sarcoplasmic reticulum (SR), • is rich in a Ca2+-binding protein, calsequestrin

42. Muscle membrane depolarization : Skeletal muscle • In order for repolarization to occur again, sodium must be actively pumped out of the cytosol by Na+/K+-ATPase pumps • The rate of muscle repolarization is affected by both the rate and density of these pumps • Higher levels of Na+/K+-ATPaseactivity are found in fast contracting muscles • Increased Na+/K+-ATPasepump density is an important adaptation to exercise

43. MUSCLE ENERGY METABOLISM • Muscle is the major consumer of fuels and ATP in the body • ATP is used for • contractile process • restoration of intracellular calcium levels • maintenance of ion gradients • Three ATPases are required • Myosin-ATPase • Ca2+-ATPase • Na+/K+-ATPase • Decreased ATP availability or inhibition of any of these ATPases will cause a decrease in muscle force production

44. ATP • The amount of ATP in skeletal muscle is only sufficient for a few seconds, so that ATP must be constantly renewed • Energy systems for muscle contraction • the creatine phosphate shuttle • anaerobic glycolysis (using blood glucose or muscle gycogen) • aerobic metabolism via oxidative phosphorylation • a reaction catalyzed by adenylate kinase (from two molecules of ADP )

45. Contractions • The energy systems that synthesize ATP are not equivalent, and directly affect the amount and duration of power output from the contracting muscle • There are two main types of contractions • Short-duration, high-power output contractions • Low-intensity, long-duration contractions

46. Short-duration, high-power output contractions • High force output can only be maintained for a short period of time • Contractions at maximal power levels depend on • high myosin-ATPase • rapid ATP resynthesis by using the high energy compound creatine phosphate • Creatine is synthesized from arginine and glycine and is phosphorylated reversibly to creatine-P by the enzyme creatine (phospho) kinase (CK or CPK) • CK : Creatine + ATP Creatine-P + ADP • MM (skeletal muscle) • BB (brain) • MB (enriched in cardiac tissue)

47. Short-duration, high-power output contractions (cont.) • The level of creatine-P in resting muscle is several-fold higher than that of ATP • Thus, ATP concentration remains relatively constant during the initial stages of exercise • Creatine phosphate stores decline rapidly during the first minute of high power output muscle contraction • ATP is also replenished by adenylate kinase (myokinase) as follows: • Adenylate kinase: 2ADP ATP + AMP

49. Clinical correlation:CK and CK-MB • Total CK:Diagnosis muscle disorders • CK-MB : Diagnosis Myocardial Infarction

50. Clinical correlation:Creatinin • Creatine phosphate is unstable and spontaneously cyclizes to form creatinine, which is excreted in theurine • The spontaneous production of creatinine occurs at a constant rate and isproportional to body muscle mass • Thus, the amount of creatinine excreted eachday (the creatinine clearance rate) is constant and can be used as an indicator ofthe excretory function of the kidneys