Biochemistry of Muscle Contraction

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Biochemistry of Muscle Contraction

Fred P. Guillergan M.D., FPCP

Outline


histology and biochemistry of muscles (Striated & smooth) – Myosin – Actin, Tropomyosin, Troponin – Accessory proteins of muscles Biochemical events in muscle contraction Calcium, Ca2+-binding proteins and Ca2+ channels in muscle contraction Biochemistry of Cardiac & Smooth muscle contraction Energetics of muscle contraction

☻Able to understand the normal anatomy and physiology of different types of muscles ☻ Provide knowledge of the metabolic processes in muscles ☻ Provide bases for understanding how muscles react to certain drugs or foreign substances ☻ Able to understand diseases of the muscles

Biomedical Importance of the Biochemistry & Molecular Biology of Muscle

Three Types of Muscles
☻Skeletal muscle ☻Cardiac muscle ☻Smooth muscle

Skeletal muscle fiber

• Many myofibrils Embedded in sarcoplasm • Enclosed by sarcolemma: electrically excitable membrane • Supplied by energy compounds (ATP, phosphocreatine) & Glycolytic enzymes • Multinucleated with many mitochondira • Intimately associated with T tubules and SR

View from an electron microscope

actin

myosin

Thick filaments
-55% of protein by wt.
Papain - assymetric hexamer - mol. Mass of 460 kDa - has actin binding site Light chains - has ATP binding site w/ ATPase activity

Trypsin
Heavy chains

Thin filaments (G-actin)
- monomeric (G) actin - 25% of muscle protein by wt. - polymerizes at physiologic ionic strength with Mg2+

F-actin
-6-7 nm thick

- pitch every 35.5 nm

Tropomyosin & Troponins

Tropomyosin – fibrous molecule, a dimer (ά and β) attach to F-actin Troponin – TpT (binds to tropomyosin and the other troponins)

– TpI (inhibits the F-actin-myosin interaction)
– TpC (calcium binding polypeptide)

Accessory Proteins in muscles


* Titin  – largest protein known (human heart isoform has 27,000 amino acids) – Filamentous protein that reaches from the Z

line to the M line – Involved in the assembly of A-band proteins – Regulates resting muscle tension – Contains PEVK (Pro, Glu, Val, Lys) repeats

Accessory muscle proteins


* Nebulin – extends from the Z line along the length of actin filament * ά actinin – anchors actin to the Z lines * Desmin – bind myobrils side by side and attaches it to the cell surface * Dystrophin – involved in attachment to the plasma membrane

Biochemical events in one cycle of muscle contraction
1. Relaxation phase – hydrolysis of ATP in S1 head of myosin forming a complex of ADP-Pi-myosin (energized) 2. Stimulation of muscle contraction (involving Ca2+) – actin-myosin-ADP-Pi 3. Release of Pi initiating power stroke & release of ADP 4. ATP binds to S1 forming actin-myosin-ATP 5. Actin is released (key component of relaxation)

Mechanics of Muscle Contraction

Regulation of muscle contraction mechanism 1. TpI prevents binding of myosin head to its F-actin by altering the conformation of F-actin via the tropomyosin molecules 2. Rolling the tropomyosin into a position that directly blocks the attachment sites on F-actin

ATP Hydrolysis as Source of Energy

Calcium in muscle contraction
* Ca2+ regulates muscle contraction
– TpI may alter the conformation of F-actin or directly blocks the F-actin * Source of Ca2+  – Extracellular (dihydropyridine receptor) and Sarcoplasmic reticulum (ryanodine receptor) * Ca2+ in resting muscle – Sarcoplasmic Ca2+ level is 10-7 mol/L or less

Release of Calcium

Cardiac muscle


* striated, has intrinsic rhythmicity, syncytial  * well developed T tubules, less extensive SR  * ECF Ca2+ important in contraction  * cAMP has prominent role in intracellular Ca2+ modulation  * plasmalemma contains a variety of receptors (ά and β adrenergics)

Transmembrane proteins for Ca2+ transport
1. Ca2+ channels – allow calcium only a). L-type or slow channel- major portal of entry, regulated by cAMP-dependent protein kinases...
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