Skeletal Muscle Tissue Notes

Introduction and Learning Objectives

These notes provide a comprehensive overview of skeletal muscle tissue, covering its histological structure, functional components, and the mechanisms of contraction and regulation.

• Compare and Contrast Muscle Tissue Types: Differentiate the histological structures of skeletal, cardiac, and smooth muscle tissues.

• Skeletal Muscle Fiber Structure: Understand the organization of skeletal muscle fibers, including the location and roles of epimysium, perimysium, and endomysium.

• Components and Contraction: Describe how myofibers, myofibrils, sarcomeres, myofilaments, T-tubules, sarcoplasmic reticulum, and the neuromuscular junction contribute to muscle contraction.

• Dystrophin's Role: Explain the function of dystrophin molecules in anchoring myofibrils to the sarcolemma.

Overview of Muscle Tissue

• Muscle tissue is specialized for shortening or contraction to produce movement of body parts.

• It is highly cellular and richly supplied with blood vessels.

Types of Muscle Tissue

There are two main categories:

• Striated Muscle: Possesses regularly arranged contractile units.

  • Skeletal Muscle:

    • Contraction: Quick, vigorous, and under voluntary control.

    • Cells: Long, cylindrical, multinucleated cells with peripherally placed nuclei.

    • Function: Used for locomotion, mastication (chewing), and phonation (speech).

  • Cardiac Muscle:

    • Contraction: Involuntary, vigorous, and rhythmic.

    • Cells: Elongated, branched cells with a single, centrally placed nucleus and intercalated discs at the ends.

    • Function: Responsible for the heart's contractions and relaxations.

• Non-striated Muscle: Possesses contractile machinery, but it is irregularly arranged.

  • Smooth Muscle (Visceral Muscle):

    • Cells: Fusiform (spindle-shaped) with a central nucleus.

    • Contraction: Involuntary, slow, and long-lasting.

    • Function: Found in the digestive tract, moving food along.

Comparison of Different Muscle Types

Skeletal Muscle Tissue: General Characteristics

• Definition: Muscles of the body that are attached to the bones of the "skeleton."

• Function: Contraction permits movements of extremities, eyeballs, tongue, chest cavity, and more.

• Control: Contractions are voluntary, meaning they are consciously controlled.

• Force: Skeletal muscles can exert tremendous forces. For example:

  • Uncontrolled contractions (spasming) during seizure activity can snap the diaphysis (shaft) of long bones.

  • The human calf muscle can, on its own, withstand forces of over a ton.

Terminology

Derived from the Greek root "sarkos," meaning "flesh":

• Sarcolemma: The cell membrane of a muscle fiber.

• Sarcoplasm: The cytoplasm of a muscle fiber.

• Sarcoplasmic Reticulum (SR): The specialized endoplasmic reticulum of a muscle fiber.

• Muscle Fiber: A muscle cell.

Location

• Usually attached to bone.

• The periosteum (connective tissue covering bones) is continuous with the tendon (connects muscle to bone), which is continuous with the fascia (sheath of connective tissue).

Cell Structure

• Skeletal muscle fibers are long, cylindrical, parallel fibers arranged as bundles within bundles.

• The hierarchical construction is:

  • Actin & myosin form myofilaments.

  • Bundles of myofilaments form myofibrils.

  • Bundles of myofibrils form muscle fibers (muscle cells).

  • Bundles of muscle fiber bundles form the entire muscle.

Myofibril Arrangement

• Myofibrils densely fill the muscle cell from end to end.

• They are arranged in an orderly fashion, exhibiting visible dark striations.

Nuclei

• Skeletal muscle cells are multinucleated.

• The nuclei are typically located peripherally, near the sarcolemma.

Contraction and Control

• Contraction: Vigorous, of relatively short duration, with fibers contracting independently.

• Control: Voluntary contraction.

• Alternative Names: Voluntary, striated muscle.

Vascular Supply

• Skeletal muscle has a good blood supply, which varies with activity.

• It ranks second among muscle tissues in terms of vascular supply.

Skeletal Muscle Tissue: Structure

• Skeletal muscle structure is described as "bundles within bundles within bundles."

• Each individual skeletal muscle fiber is a single large cell formed by the fusion of $10$ to $100$ (hundreds) embryonic muscle cells (myoblasts).

  • Consequently, a skeletal muscle fiber has $10$ to $100$ nuclei.

  • A fiber can range from $10$ to $100<br>ometer$ in width and $1$ to $300<br>ometer$ in length, with an average length of $100<br>ometer$.

Connective Tissue Layers

These layers provide structural support, allow for force transmission, and compartmentalize the muscle.

• Endomysium: Encapsulates each individual muscle fiber (cell).

  • Inner layer: Mostly laminin.

  • Middle layer: Collagen Type IV.

  • Outer layer: Collagen Type I and Type III.

  • Significance: Since skeletal muscle fibers are rarely as long as the entire muscle, this collagen is crucial for the muscle's ability to generate useful force.

• Perimysium: Surrounds a bundle of muscle fibers, forming a structure called a fascicle.

  • It is a thin layer of areolar connective tissue.

• Epimysium: Encloses groups of fascicles, forming an individual muscle.

  • It is a layer of dense connective tissue.

  • Some skeletal muscles can be divided into entire muscles and heads of skeletal muscles, both surrounded by epimysium.

• Fascia: A tough layer of fibrous connective tissue that wraps each individual muscle.

  • It is located outside the epimysium, surrounding and separating muscles.

  • It is continuous with tendons and the periosteum of bones.

Summary of Connective Tissue Structure

1. Muscle fibers are cells surrounded by endomysium.

2. Fascicles (bundles of muscle fibers) are surrounded by perimysium.

3. Muscles & heads are surrounded by epimysium.

4. Fascia is outside the epimysium, surrounding and separating the muscles.

Skeletal Muscle Tissue: Muscle Fibers

• Muscle fibers are the basic functional units of the muscle itself.

• Muscle fibers are composed of smaller sub-units called myofibrils, which are $1$ to $3 ometer$ in diameter and as long as the muscle fiber.

  • Development: During early development, embryonic myoblasts (single, spherical/elongated, uninucleated precursor cells), each with its own nucleus, fuse with up to hundreds of other myoblasts to form multinucleated skeletal muscle fibers.

  • Purpose of Multiple Nuclei: Multiple nuclei mean multiple copies of genes, allowing for the production of large amounts of proteins and enzymes necessary for muscle contraction.

• The functional unit of a skeletal muscle fiber is the sarcomere.

Sarcoplasmic Reticulum (SR)

• Structure: A network of tubules and saccules located between the myofibrils within a skeletal muscle fiber, separating myofibrils from each other.

• Nature: It is a specialized smooth endoplasmic reticulum (SER).

• Distinguishing Features: Characterized by the presence of a calcium-activated ATPase and gated calcium channels.

  • The calcium-activated ATPase concentrates $Ca^{2+}$ within the saccules of the SR.

  • The calcium channels release $Ca^{2+}$ to initiate muscle contraction.

• Function: Stores, releases, and retrieves $Ca^{2+}$ ions.

Sarcomere: Structure and Components

• A highly organized arrangement of contractile myofilaments (actin and myosin), along with other support proteins.

• Each sarcomere is approximately $2<br>ometer$ in length, arranged in a three-dimensional cylinder-like fashion, and bordered by structures called Z-discs (or Z-lines).

Myofilaments

Each myofibril contains two types of myofilaments:

• Thin Filaments (Actin):

  • Composed of actin and its troponin-tropomyosin complex.

  • Project from the Z-discs toward the center of the sarcomere, forming strands thinner than myosin.

  • They are isotropic (transparent to polarized light), forming the I-bands.

  • Typical dimensions: $0.007<br>ometer$ across and $1<br>ometer$ long.

• Thick Filaments (Myosin):

  • Composed of myosin strands and their multiple heads.

  • Project from the center of the sarcomere, towards but not all the way to the Z-discs.

  • They have more mass and are thicker than thin filaments.

  • They are anisotropic (opaque to polarized light), forming the A-bands.

  • Typical dimensions: $0.015<br>ometer$ thick and $1.5<br>ometer$ long.

Z-disc (Z-line)

• Anchoring Plate: A plate of $ext{\alpha}$-actinin that anchors the thin filaments.

• Microscopic View: At extremely high magnification ($X ext{ }150,000$), the Z-line appears as a puckered disk composed of a fine network of $ext{\alpha}$-actinin fibers.

I-bands

• Composition: Sections of the myofibril that consist only of thin filaments.

• Appearance: Pale under the light microscope (light bands).

• Division: The Z-disc splits the I-band into halves.

• Dimensions: The resting length of an I-band is $0.8<br>ometer$; each half is $0.4<br>ometer$ long.

• Contraction: Decrease in length during contraction.

A-bands

• Composition: Sections of the myofibril that contain thick filaments (and overlapping thin filaments).

• Appearance: Dark under the light microscope (dark bands).

• Dimensions: Approximately $1.5<br>ometer$ wide.

• Contraction: Do not shorten during contraction.

Myofilament Anchoring

• Thin Filaments: Anchored by one end to each side of a Z-disc; the other end is free.

• Thick Filaments: Each thick filament is attached to a Z-disc by a filament of titin.

  • The elasticity of titin is responsible for the passive rebound of a stretched muscle.

• Two groups of thin filaments run parallel, one on each side of a Z-disc.

• Thick filaments lie between the thin filaments, spanning the gaps between the free ends of the thin filaments.

H-band

• Composition: The portion of the A-band that contains only thick filaments.

• Dimensions: Usually only $0.3<br>ometer$ wide.

• Appearance: Can sometimes be seen at the highest magnification of a light microscope as a slightly paler line in the middle of the A-band.

• Contraction: Shorten during contraction.

M-band (M-line)

• Location: A thin dark line in the middle of the H (or A) band.

• Function: Contains fine transverse filaments that link the thick filaments together, maintaining their alignment and anchoring myosin during contraction.

Sarcomere Definition and Connections

• The sarcomere is the part of a myofibril between two Z-lines.

• It includes two half I-bands and one A-band.

• A myofibril consists of many sarcomeres arranged end-to-end.

• Inter-myofibril Connection: The Z-lines of one myofibril are connected to the Z-lines of neighboring myofibrils by $11<br>ometer$ intermediate filaments of desmin, a protein peculiar to muscle cells.

• Sarcolemma Anchoring (Costameres): The Z-lines nearest to the cell membrane are anchored to it by protein complexes called costameres.

  • The $ext{\alpha}$-actinin plate is connected to a membrane protein called integrin by a protein called vinculin.

  • Clinical Note: Defective vinculin is lethal in the first trimester.

Muscular Dystrophy and Costamere Importance

• Costameres: Sub-membranous, Z-line associated structures found in striated muscle.

• Dystrophin's Role: The filamentous protein dystrophin connects points on the thin filaments (adjacent to the Z-disk and closest to the cell membrane) to dystroglycan in the cell membrane.

• Basal Lamina Connections:

  • Dystroglycan bonds to laminin in the basal lamina.

  • Integrin seems to bond directly to collagen Type IV in the basal lamina.

• Muscular Dystrophy: Defective dystrophin or dystroglycan causes a slow deterioration of muscle, leading to death before age $30$. It is a rare condition.

Morphology under the Microscope

• The overlapping structure of thin and thick filaments, held together by chemical cross bridges, gives skeletal muscle a characteristic banded or striped appearance under the microscope.

• These alternating light (I) and dark (A) bands are called striations, which give skeletal muscle its more accurate name: voluntary, striated muscle.

T-tubules & Triad

• T-tubules (Transverse Tubules):

  • Structure: Invaginations of the sarcolemma that run transversely across the cell between myofibrils.

  • Location: Situated next to the boundary between the A and I bands (A–I junction).

  • Continuity: The membrane of a T-tubule is an extension of the sarcolemma.

  • Contents: The contents of the T-tubule are tissue fluid, which contains both $Na^{+}$ and $Ca^{2+}$.

• Triad:

  • Composition: An enlarged cistern (terminal cisterna) of the sarcoplasmic reticulum lies close to each side of a T-tubule.

  • The T-tubule and the two cisternae of the SR (one on each side) together form a triad.

Muscle Contraction: The Sliding Filament Model

• Muscle contraction occurs through the sliding of thin filaments over and between thick filaments towards the center of the sarcomere.

• This action shortens the distance from Z-disc to Z-disc.

• Contraction critically depends on the interaction of actin (thin filament) and myosin (thick filament).

Myosin and Actin Proteins

• Myosin (Thick Filament):

  • Structure: A protein shaped like two golf clubs with their shafts twisted together to form a dimer.

  • Assembly: Hundreds of these dimers combine side-to-side to form a thick filament.

  • Heads: The heads of the myosin molecules stick out from the thick filament, forming cross-bridges.

• Actin (Thin Filament):

  • Monomer (G-actin): A globular protein, the product of a single gene.

  • Polymer (F-actin): A chain of G-actin units.

  • Thin Filament Basis: A double helix of two F-actin filaments twisted around each other forms the basis of a thin filament.

Sliding of Filaments by Cross Bridges

• Mechanism: The sliding of filaments is produced by the actions of cross bridges.

  • Cross bridges are myosin proteins that extend out (forming arms that terminate in heads) toward actin.

• Myosin Head Function:

  • Each myosin head contains an ATP-binding site.

  • The myosin head functions as a myosin ATPase, hydrolyzing ATP.

  • Each G-actin unit has a myosin binding site for binding the head of a myosin molecule.

  • This binding flexes the head of the myosin molecule, producing a powerstroke and thus contraction.

• Powerstroke Cycle: The myosin motor protein possesses ATPase activity and functions in a cyclical manner that couples ATP binding and hydrolysis to a conformational change in the protein, known as the 'powerstroke cycle'.

Regulation of Contraction

• Key Regulators: Cross-bridge attachment to actin is regulated by tropomyosin and troponin.

  • Tropomyosin: A protein that lies within the groove between the double rows of G-actin in the thin filament.

  • Troponin: Attached to tropomyosin, it serves as a critical switch for muscle contraction and relaxation.

• In Relaxed Muscle: Tropomyosin physically blocks the myosin binding sites on actin, preventing cross-bridge formation.

Excitation-Contraction Coupling (ECC)

This is the process linking an electrical signal (action potential) to muscle contraction.

1. Neuromuscular Junction (NMJ): Acetylcholine (ACh), a neurotransmitter, is released.

2. End-Plate Potential (EPP): ACh binds to acetylcholine-gated sodium channels on the postsynaptic membrane (sarcolemma), causing $Na^{+}$ diffusion into the muscle fiber, which produces an end-plate potential (EPP) (depolarization).

3. Action Potential Generation: If the depolarization is sufficient to reach threshold, it creates an action potential (AP) (from $-70 ext{ }mV$ to $+30 ext{ }mV$).

4. AP Propagation: APs travel across the sarcolemma and down the T-tubules.

5. T-tubule Depolarization: Depolarization of the T-tubule membrane opens Dihydropyridine Receptors (DHPRs), which are voltage-gated cation channels on the T-tubule membrane.

   • This causes $Na^{+}$ and a small amount of $Ca^{2+}$ to flow into the cell, which in turn opens more DHPRs.

6. SR $Ca^{2+}$ Release: DHPRs are directly linked to Ryanodine Receptors (RyRs) in the membrane of the SR terminal cisternae.

   • Activation of DHPRs causes RyRs to open, leading to a massive release of stored $Ca^{2+}$ from the SR into the muscle fiber's cytosol.

7. Troponin-Tropomyosin Shift: The released $Ca^{2+}$ attaches to troponin.

8. Cross-Bridge Formation: This $Ca^{2+}$-troponin binding causes a conformational change in the tropomyosin-troponin complex, moving tropomyosin away from the myosin binding sites on actin (unmasking them).

9. Contraction: Cross bridges (myosin heads) attach to actin, initiating the powerstroke cycle and muscle contraction.

Muscle Relaxation

1. ACh Degradation: Acetylcholinesterase degrades acetylcholine in the synaptic cleft, ending the neural signal.

2. RyR Closure: $Ca^{2+}$ release channels (RyRs) on the SR close.

3. $Ca^{2+}$ Reuptake: $Ca^{2+}$ is actively pumped back into the sarcoplasmic reticulum through $Ca^{2+}$-ATPase pumps (SERCA pumps).

4. Choline Recycling: Choline, a product of ACh degradation, is recycled to make more ACh.

5. Troponin-Tropomyosin Reestablishment: Lower cytosolic $Ca^{2+}$ concentrations cause $Ca^{2+}$ to detach from troponin. Troponin then allows tropomyosin to move back over the myosin-binding sites on actin.

6. Relaxation: Myosin heads can no longer bind to actin, and the muscle relaxes.

Sources of Energy for Contraction

• ATP from Mitochondria: ATP is primarily supplied by mitochondria, which are located both around the myofibrils and under the sarcolemma.

• Phosphocreatine Reserve: There is a small reserve of phosphocreatine which can rephosphorylate ADP to ATP for several seconds (e.g., long enough to fuel a $100 ext{ }m$ dash).

• Glycolysis: Some ATP is supplied by glycolysis in the cytosol, but the buildup of lactic acid limits this process to about a minute or so.

Short Account of Contraction and Relaxation

Contraction Summary

Acetylcholine $o$ (+) Acetylcholine-gated sodium channels $o$ (+) $Na^{+}/K^{+}$ ATPase (contributes to ion gradient and depolarization) $o$ cell depolarizes by $Na^{+}$ influx $o$ Action Potentials $o$ (+) dihydropyridine receptors (DHPRs) in T-tubule membrane $o$ (+) ryanodine receptors (RyRs) $o$ $Ca^{2+}$ into cytosol $o$ $Ca^{2+}$ shrinks troponin (causes conformational change) $o$ moves tropomyosin to unmask myosin binding sites on actin $o$ muscle contracts!

Relaxation Summary

Cholinesterase $o$ destroys acetylcholine $o$ (-) Acetylcholine-gated sodium channels $o$ (-) ($Na^{+}/K^{+}$ ATPase reduces activity, pumps out $Na^{+}$ to repolarize cell) $o$ Cell repolarizes $o$ (-) (closes) dihydropyridine receptors $o$ $Ca^{2+}$ pump pumps $Ca^{++}$ into sarcoplasmic reticulum $o$ troponin swells (returns to original conformation as $Ca^{++}$ leaves) $o$ troponin positions tropomyosin over myosin-binding sites on actin $o$ muscle relaxes!

Summary of Key Points

• Skeletal muscle fibers are very long, multinucleated cells.

• Perimysium surrounds fascicles, which contain arterioles.

• Sarcoplasmic reticulum surrounds myofibrils inside each fiber.

• Myofibrils are long arrays of sarcomeres.

• Acetylcholine from the motor end plate allows $Na^{+}$ into the cell.

• $Na^{+}$ influx opens dihydropyridine receptors (DHPRs) and depolarizes the fiber.

• DHPRs open ryanodine receptors (RyRs).

• RyRs allow $Ca^{++}$ into the cytosol to interact with troponin and initiate contraction.

• Cytosolic $Ca^{++}$ concentrations control muscle contraction and relaxation.

• Cytosolic $Ca^{++}$ concentrations are precisely controlled by the SR.

• ATP allows myosin heads to move along F-actin, causing contraction.