Lecture 6. Skeletal Muscle contractility by variablepitch349


									Axiom #5 Knowledge is power!

Lecture #5. Muscle contraction Skeletal Muscle fibers Fig. 1. P 192.
Glucose from glycolysis



Anaerobic and Aerobic metabolism in exercise
• Fast twitch fibers have limited number of mitochondria, Therefore they have limited aerobic capacity. Most energy is from ATP generated anaerobically as a result of glycolysis. Buildup of lactic acid. E.g. running and lifting weights • Slow twitch fibers: primarily aerobic: ATP generated by by electron transport and TCA cycle in mitochondria. Do not produce lactic acid. E.g fast walking and bicycling

Lecture 5. Skeletal Muscle contractility
Muscles can be optimized for strength (fast twitch)
Characteristics of Maximal Strength Muscle Cells •high volume of contractile protein. Large cell diameter: holds more contractile protein (actin and myosin). •To make more room for actin and myosin, mitochondrial density should be minimized to that necessary to maintain resting cell function. •Since fat can only be metabolized aerobically, high levels of fat cleaving enzymes in the cytoplasm are also unnecessary. •The capacity for anaerobic glycolysis should be high to allow brief but high capacity energy production without oxygen

Muscles can be optimized for endurance
• Characteristics of Fatigue Resistant Muscle Cells
• Prime Example: Heart cells, smaller in diameter than skeletal muscle cells. This results in very short diffusion distance between oxygen molecules coming from capillaries and the mitochondria where they are used. Surrounding network of capillaries is extremely well developed: facililitates even and rapid oxygen distribution to all myocardial cells. The mitochondrial density of heart cells is extremely high, 20-25% of cell volume in adults. Mitochondria use oxygen to metabolise food and produce ATP. The cytoplasmic enzymes responsible for breaking down fatty acid molecules into 2 carbon fragments that can enter the mitochondria are present in high concentrations. Contractile protein makes up about 60% of cell volume. The ATPase subtype found in heart is slower than that seen in skeletal muscle. Consequently, the rate of force development is slower, although absolute tension/cell diameter is the same.





Skeletal muscle cells arise by cell fusion

Fig 9.56

Crouch and Tato. J. Cell Biol. 125:1142. 1994 Mouse nucleus

• Mix quail and mouse muscle cells • Cultured muscle cells (myotubes) arise from fused muscle cell precursors (myoblasts) • Single cells with multiple nuclei

Quail nucleus

Figure 9.57 The structure of skeletal muscle


Muscle fibers (cells)
• Nuclei are on the periphery of fibers Note each cell or fiber is multinucleated


HYPERTROPHY - Increased size of an organ or structure. An adaptive response of increasing cellular mass to maintain viability at higher levels of metabolic activity. Cells do not proliferate. The increase in cell mass is brought about by increasing the numbers of subcellular organelles Hyperplasia: An increase in the number of cells in an organ or tissue (excluding tumor formation) which may lead to an increase in the volume of the organ or tissue

Banding pattern due to alignment of myofilaments: . I band: isotropic, light A band: anisotropic, dark
This cardiomyocyte has been stained with three different labels to show sarcomeric structure. The colors shown represent tropomodulin (blue), alpha-actinin (red), and actin filaments (green). Both tropomodulin and alphaactinin were labeled with antibodies, whereas actin filaments were labeled with fluorescent-tagged phalloidin.

A single sarcomere. The fundamental unit of striated muscle contractility. Fig. 9.57

• • • • •

A band I band H band M line Z line


Sarcomere proteins
• Thick filaments: Myosin: mechanoenzyme that cyclically with actin thin filaments Thin filaments: Actin: major subunit of actin filaments Tropomyosin: binds in grove of actin helix, stabilizes modulates myosin binding Tropomodulin: actin filament pointed end capper Troponin T,I,C. regulate myosin binding T: binds tropomyosin I: inhibitory C: binds Ca2+ Nebulin: length of thin filament, stabilizing effect interacts




Other sarcomeric proteins
• a-actinin: crosslinks actin at the Z-disk

• Titin: molecular spring. Enormous. ~ 3 million daltons. 1 um, spans half sarcomere from Z disk to M line

Cross section through sarcomere showing interdigitating thick and thin filaments
Myosin thick filament

Actin thin filament


What happens to the sarcomere during contraction?
Where are + ends of actin thin filaments?



•Sliding filament theory Huxley, A and H.

Changes in relaxed and contracted sarcomere

Fig. 9.59

The shortening of the sarcomere during Fig. muscle contraction

H zone is shortened I band is unchanged A band is unchanged


What are the molecular mechanisms that cause sliding of thin filaments past thick filaments?

• Swinging crossbridge theory
Myosin undergoes an ATP-dependent confirmations change that enables force to be produced by cyclic interactions with actin filaments.

Myosin in sarcomere, S1

Regulated skeletal muscle myosin movement
• • • • • • Myosin: red Actin: brown Tropomyosin: blue Troponin: magenta Calcium: pea ATP/ADP green

Thin filaments in skeletal muscle
• Myosin binding site on actin is hindered in absence of Ca2+. • Transient release of Ca2+ allows Tn/TM complex to roll laterally, thereby exposing the myosin binding site.

Actomyosin interactions
Myosin walk toward the barbed end of actin filaments Mechanochemical energy comes From hydrolysis of ATP

+ ATP, weak binding
-ATP high affinity binding

-Tropomyosin and the -Troponins modulate actomyosin

Questions you should think about
• What regulates F-actin length? • Are actin filament dynamic?

• Is myosin-II processive or nonprocessive • Lever Arm (neck); the longer the neck, the longer the step. Short necks have short steps. Step size of 5-10 nm.

Cardiac or heart muscle resembles skeletal muscle in some . ways: it is striated and each cell contains sarcomeres with sliding filaments of actin and myosin

Muscle Pathologies

Heart Anatomy

Inferior Vena Cava

Dilated Cardiomyopathy
- Loss of myocytes
-Decrease in contractile proteins - Myofilament disarray - Interstitial fibrosis


Heart from a patient with dilated cardiomyopathy. Note the dilated left ventricle

Example 2. Hypertrophic Cartiomyopathy This is a heart from a patient with hypertrophic dilated cardiomyopathy. Note the thickness of the left ventricular wall. A normal heart is shown on the left for comparison. IVS=intraventricular septum.

The main feature of Hypertrophic Cardiomyopathy is an excessive thickening of the heart muscle (hypertrophy literally means to thicken).

Hypertrophic Cardiomyopathy
This condition is believed to inhibit heart cells' ability to contract. The cells react by releasing more calcium, which stimulates contractions but also makes the heart grow so big that parts of it can't get enough oxygen. Arrhythmias follow, which can lead to heart failure Microscopic examination of the heart muscle in Hypertrophic Cardiomyopathy shows that it is abnormal. The normal alignment of muscle cells is absent and this abnormality is called myocardial disarray

Heart muscle can only exhibit hypertrophy, cells don’t regenerate
Implications for heart attack? Cardiomyoathy?

Can adult heart cells be induced to differentiate?
In exercise, there is actual damage to the muscle fiber followed by a repair process. One compound believed to be released as part of this repair process is insulin-like growth factor type 1 or IGF-1. It is believed that IGF-1 stimulates small single cells that lie adjacent to the muscle fiber called satellite cells to proliferate (reproduce themselves). These cells are a vital part of the regenerative capacity of muscle when the muscle is injured. These single cells will fuse with a damaged muscle fiber and become a new muscle fiber segment replacing that which was destroyed. It will then produce all the proteins necessary to become a part of the contractile apparatus of the muscle fiber as well as the structural proteins needed to stabilize the muscle membrane increasing resistance to damage.

Tuesday, Muscular Dystrophy

Figure 7. Hypothetical model suggesting how
muscle activity and muscle agrin may participate in organization of the cytoskeleton of muscle fibers outside (A) and inside (B) NMJs. (A) Muscle activity regulates expression, secretion, and/or processing of muscle agrin. Muscle agrin then binds in an autocrine way to -dystroglycan (1). Activity may also affect -dystroglycan itself (2), or downstream effectors of -dystroglycan (3). Through these effects on the dystroglycan complex that involve electrical and mechanical signals in the muscle, links between the extracellular matrix and the cortical actin network become stabilized. (B) At NMJs, similar mechanisms operate with several additions. Here, neural agrin, not present outside, binds to a receptor complex containing muscle-specific kinase (MuSK) and induces the appearance of synapsespecific aggregates of AChRs, ß2-laminin, rapsyn, and utrophin. These proteins (and others) then become linked to the cortical actin network and are stabilized by muscle activity and muscle agrin as in A. -and ß-DG, - and ß-dystroglycans; RATL, rapsyn-associated transmembrane linker (hypothetical protein).

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