Muscle tissue

Muscle tissue is a soft tissue that is primarily composed of long muscle fibers. The coordinated interaction of the myofilaments actin and myosin within the myocytes gives muscle tissue the ability to contract. Depending on the intracellular arrangement of these myofilaments, muscle tissue is classified as either striated (skeletal and cardiac) or nonstriated (smooth) muscle. The myofilaments of striated muscle are arranged into sarcomeres while smooth muscle myofilaments lack a specific arrangement. The underlying mechanisms of contraction (excitation-contraction coupling and the sliding filament mechanism) are similar in all muscle types. Skeletal muscle is under voluntary control of the somatic nervous system. Smooth muscle is under involuntary control of the autonomic nervous system and external stimuli (e.g., chemical, mechanical). It possesses greater elasticity and is present in the walls of hollow organs (e.g., stomach, bladder, uterus), the walls of vessels, and the respiratory and urinary tracts. Cardiac muscle is also under involuntary control of cardiac pacemaker cells and forms the walls of the cardiac chambers (myocardium).

Overview ^[1]

• Classification
  • Striated muscle fibers: skeletal and cardiac muscle
  • Nonstriated muscle fibers: smooth muscle
• Function: produce a muscle contraction or generate tension in order to move or to resist a load
• Origin: mesoderm

Muscle cell structures ^[1]

Sarcolemma (myolemma)

• Definition: muscle cell membrane; , which contains membrane invaginations
• Characteristics
  • Transverse tubules (T-tubules)
    • Transverse tubular invaginations of the sarcolemma of striated muscle cells
    • Transmit the action potential (AP) to the sarcoplasmic reticulum; (close proximity of T-tubules to adjacent terminal cisternae allows for direct transmission of APs to the sarcoplasmic reticulum → quick release of Ca²⁺ for muscle contraction)
    • Responsible for synchronization of AP transmission and muscle contraction
  • Caveolae
    • Invaginations in the sarcolemma of smooth muscle cells, located close to the sarcoplasmic reticulum
    • Contain various receptors and ion channels involved in signal transduction

Sarcoplasm

• Definition: muscle cell cytoplasm
• Contents
  • Myofibrils (consisting of myofilaments)
  • Glycosomes (granules of stored glycogen)
  • Myoglobin
  • Ca²⁺ (to initiate contraction by binding troponin)

Sarcoplasmic reticulum (SR)

• Definition: muscle cell endoplasmic reticulum, which forms a network of L-tubules
• Characteristics
  • Terminal cisternae: the ends of L-tubules which encircle myofibrils and lie adjacent to T-tubules
  • Triad (skeletal muscle): one T-tubule and two terminal cisternae
  • Diad (cardiac muscle): one T-tubule and one terminal cisterna
• Stores Ca²⁺

Myofilaments

• See section below.

Comparison of muscle cell types ^[1]

Myofilaments are protein fibers consisting of thick (myosin) and thin (actin) filaments and are responsible for the contractile properties of muscle cells.

Actin myofilaments (thin filaments) ^[1]

Structure

• Actin myofilaments are thin filaments composed of actin molecules, regulatory proteins, and nebulin.
• Regulatory proteins prevent permanent interaction between myosin and actin.
  • Proteins that block myosin-binding sites
    • Tropomyosin: in both striated and smooth muscle
    • Caldesmon and calponin: only in smooth muscle
  • Proteins that interact with Ca²⁺
    • Troponin: in striated muscle
    • Calmodulin: in smooth muscle
• Nebulin
  • A protein integrated into actin myofilaments
  • Responsible for stabilizing the length of actin myofilaments

Function

• Thin filaments form a foundation over which myosin slides during contraction.

Troponin proteins in cardiac muscle have a different structure than in skeletal muscle. In myocardial infarction, cardiac myocytes are damaged as a result of absolute oxygen deficiency and release their intracellular content into the bloodstream. An increase in blood cardiac troponin levels thus indicates cardiac muscle tissue damage.

Myosin myofilaments (thick filaments) ^[1]

Structure

• Contain ∼ 250 myosin molecules
• Muscle myosin molecules (myosin II) ^[2]
  • Various isoforms occur in different muscle types and determine the speed of contraction
  • Consist of two heavy and two light protein chains
  • Domains
    • Head: has both an actin and ATP binding site (which also has ATPase activity)
    • Neck: Two light protein chains attach to the heavy protein chains, which serve to regulate the myosin head.
    • Tail: Myosin heavy chains are wound around each other in a coil-like structure, with myosin heads protruding on both sides.
  • Myosin heads have a binding site for actin and a binding site for ATP (which also has ATPase activity).

Function

• Slides along actin filaments which is driven by ATP hydrolysis

Both striated and smooth muscle cells mediate contractions via actin and myosin.

Mutations in the genes encoding β-myosin heavy protein chain or cardiac myosin binding protein C are the underlying cause of familial autosomal dominant hypertrophic obstructive cardiomyopathy.

Comparison of contractile filaments between muscle cells ^[1]

Overview

• Striated and smooth muscle have similar contraction mechanisms, but with a few important differences.
• This section provides a general overview of the main principles of muscular contraction.
• See the sections below for details on individual muscle types.

Excitation-contraction coupling ^[1][3]

• Definition: a process in which an initiating stimulus (e.g., AP, chemical stimulus) triggers an increase in intracellular Ca²⁺ and subsequent myofilament shortening, resulting in muscular contraction
• Types
  • Electromechanical coupling: translation of an electrical signal from the sarcolemma into a muscle contraction
  • Pharmacomechanical coupling: triggering of a muscle contraction via agonists such as acetylcholine, noradrenaline, or histamine
• Description
  • Initiating stimulus reaches myocyte → increased intracellular Ca²⁺ → conformational changes of regulatory proteins → altered activity of regulatory proteins → interaction of myofilaments actin and myosin (see “Sliding filament theory” below.)
  • The mechanism by which the intracellular Ca²⁺ concentration increases differs for each muscle type.
    • Skeletal muscle: stimulus → opening of dihydropyridine receptors and ryanodine receptors → Ca²⁺ release from the SR ^[4]
    • Smooth muscle: stimulus → Ca²⁺ influx from the extracellular space into the muscle cell
    • Cardiac muscle: stimulus → Ca²⁺ influx from the extracellular space into the muscle cell → Ca²⁺ release from the SR

At resting position, actin and myosin are unable to interact because they are inhibited by regulatory proteins. An initiating stimulus is needed to enable interaction between the myofilaments.

Sliding filament model ^[5][6]

• Description
  • In muscular contraction, myofilaments interact with regulatory proteins and slide past each other while maintaining their length.
  • Crossbridge cycling: the process by which myofilaments slide past each other
    • A repetitive cycle of crossbridge formation and subsequent loosening between the myosin heads and thin actin filaments
    • ATP provides the energy required for crossbridge cycling.
    • Ca²⁺ initiates the crossbridge cycle.
  • For details, see “Crossbridge cycling” in the “Skeletal muscle” section.

Comparison of stimulation and contraction ^[1]

• Muscle cells require ATP as a source of energy for: ^[1]
  • Maintaining structure and ion gradients
  • Interaction between the myosin head and actin, which leads to muscle contraction
• ATP production in muscle cells ^[1]
  • Aerobic metabolism; : if sufficient O₂ is available to meet the energy demand (e.g., resting and nonstrenuous exercise states, such as walking)
  • Anaerobic metabolism: if the O₂ supply is insufficient to meet the energy demand
    • Anaerobic glycolysis and the lactic acid cycle (e.g., during sustained strenuous exercise)
    • Immediate ATP resynthesis: creatine kinase reaction and adenylate kinase reaction (sudden, short bursts of rapid movement)
  • Protein metabolism: glucose-alanine cycle (during states of catabolism such as fasting)
• See “Pathways of ATP synthesis.”

The glucose-alanine cycle provides skeletal muscle with glucose as a source of energy. The production of urea as a byproduct consumes a lot of energy, so it is less effective than the lactic acid cycle.

Overview ^[1]

• Type: striated muscle tissue
• Structure
  • Joined muscle cells form muscle fibers surrounded by endomysium.
  • Bundles of muscle fibers form fascicles surrounded by perimysium.
  • Multiple fascicles form a muscle surrounded by epimysium.
  • Muscles and the epimysium are covered by fascia.
  • Muscles attach to bones via tendons.
• Contraction regulation
  • Under voluntary control of the somatic nervous system
  • Stimulation occurs at the motor endplate.
• Function: responsible for skeletal movement

Microscopic anatomy ^[1]

• Makeup
  • Large elongated cells with multiple nuclei that are located at the periphery of the cell
  • Sarcolemma invaginations form T-tubules
  • Ca²⁺ storage in the large SR with terminal cisternae
  • Myofibrils within the myocytes: a complex structure composed of myofilaments (actin and myosin) and regulatory proteins
• Regeneration: via myosatellite cells that are interspersed between muscle fibers

“Too (2) fast to last; light and white, no air to spare.” The most important features of type 2 skeletal muscle fibers are fast-twitching, short-term activity, white appearance, and anaerobic glycolysis (no air).

Sarcomeres ^[1]

• A sarcomere is the smallest functional unit of a striated muscle fiber.
• One sarcomere is the area between two Z bands.
• During contraction, sarcomeres shorten, while myofilaments stay the same length.

Components on electron microscopy

• Z band
  • Separates one sarcomere from the other
  • Acts as an anchoring point
  • Z bands pull closer together during contraction
• M band: center of the H zone, to which myosin filaments are attached on opposite sides
• I band
  • Zone containing only actin filaments
  • Decreases in size during contraction when actin slides over myosin towards the M band
• A band;
  • Composed of three segments: a pale central segment (the H zone) surrounded by two dark outer segments
    • H zone; : a pale band on either side of the M band that contains only myosin filaments, which decreases in size during contraction when actin slides over myosin towards the M band
    • Dark bands of the outer segments (between the H zone and I bands) contain overlapping actin and myosin filaments, including the myosin heads.
  The length of a myosin filament, which may contain overlapping actin filaments (remains the same length during contraction)

The I band and H zone shorten during contraction, while the A band remains the same length.

Anchorage

• Intermediate filaments (especially desmin): crosslink Z bands and anchor in the sarcolemma
• Dystrophin-glycoprotein complex ^[7]
  • Present in the sarcolemma of skeletal and cardiac muscle cells
  • Formed by dystrophin, dystroglycan, extracellular laminin, and various other proteins
  • Connects (noncontractile) actin of the cytoskeleton with the sarcolemma and extracellular matrix
  • Clinical significance: Duchenne muscular dystrophy and Becker muscular dystrophy involve genetic defects of the dystrophin gene.
• Collagen fibrils: anchor muscle cells to the endomysium
• Titin
  • A protein between the M band and Z band that acts as a molecular spring, returning the sarcomere to its initial state after contraction
  • Limits the passive elasticity of a muscle and protects against damage ^[8]

Myofilament contraction ^[1][3]

Excitation-contraction coupling in skeletal muscle

• Site: motor endplate
• Mechanism: stimulus (AP) from efferent neuron → presynaptic voltage-gated Ca²⁺ channels open → ACh is released into the synaptic gap → ACh binds to postsynaptic ACh receptors → muscle cell depolarization that diffuses across the sarcolemma and into T-tubules → opening of voltage-sensitive dihydropyridine receptors (DHPR) in the T tubules and the mechanically coupled ryanodine receptors (RYR) in the SR → SR releases Ca²⁺ into the sarcoplasm → increased intracellular Ca²⁺

Skeletal muscle contraction results from an influx of intracellular calcium from stores in the SR. This explains the ability of skeletal muscle to contract despite treatment with calcium channel blockers, which can block an influx of extracellular calcium through DHPRs but cannot affect DHPR voltage-sensing capabilities or the resulting intracellular calcium release.

A mutation in the ryanodine receptor gene of striated muscle cells results in a ryanodine receptor that can be activated by certain substances, such as inhalation narcotics (e.g., isoflurane). This activation leads to an uncontrolled release of Ca²⁺ from the SR, which results in a continuous contraction that increases the energy and oxygen consumption of the muscle cell enormously. Affected individuals present with lactic acidosis due to increased anaerobic glycolysis and hyperthermia due to increased muscle metabolism. This life-threatening condition is called malignant hyperthermia.

Steps of the contraction cycle (crossbridge cycling) ^[1]

1. Crossbridge formation: released intracellular Ca²⁺ binds to troponin C and causes a conformational change → tropomyosin moves away from the myosin binding site of the actin filament → myosin head binds actin at a 90° angle, forming a crossbridge
2. Powerstroke of the myosin head: myosin head releases phosphate (P_i)→ myosin head tilts by 45°, pulling myosin along actin → muscle shortens (contracts) → ADP is released
3. Loosening of the crossbridge: new ATP binds to myosin head → myosin head detaches from the actin filament → myosin returns to its original position
4. Reorientation of the myosin head: hydrolysis of ATP to ADP and P_i (both remain on the myosin head) → myosin head alters its conformation (changes to a “cocked state”) → myosin returns to its original position (ready to bind to actin again)
5. Replication of the cycle
   • If the Ca²⁺ concentration in the muscle cell remains elevated, a new cycle begins with crossbridge formation.
   • Depending on ATPase activity (ATP cleavage rate per unit of time) of the myosin heavy chain, there may be ∼ 10–100 crossbridge cycles per second.
   • The more crossbridge cycles per unit of time, the faster and stronger the contraction.

Rigor mortis is the stiffening of the muscles after death, which is caused by persistent attachment of actin to myosin due to lack of ATP.

Types of muscle contraction

• Isometric contraction: The muscle contracts and generates power but does not shorten or lengthen.
• Isotonic contraction: The muscle length changes and muscle power remains constant.
  • Concentric contraction: muscle shortens
  • Eccentric contraction: muscle lengthens
• Auxotonic contraction: simultaneous change in both muscle power and length

Reflexes

• See “Spinal reflexes” in “Spinal cord tracts and reflexes”.

Skeletal muscle adaptations

Overview ^[1]

• Type: nonstriated muscle tissue
• Location
  • Walls of hollow organs (e.g., stomach, bladder, uterus)
  • Walls of arteries and veins
  • Respiratory, urinary, and reproductive tracts
• Contraction regulation: under involuntary control of the autonomic nervous system and external stimuli (e.g., chemical, mechanical)
• Function
  • Constriction (e.g., vasoconstriction, peristalsis)
  • Production of extracellular matrix

Microscopic anatomy ^[1]

• Small spindle-shaped, mononuclear cells (central nucleus)
• Sarcolemma has caveolae (membrane invaginations).
• Sarcoplasmic reticulum (SR)
  • Poorly defined
  • Ca²⁺ reservoir

Myofilament structure ^[1]

• Arrangement: irregular arrangement of actin and myosin within the sarcoplasm
• Anchoring: attached to the cell membrane via adhesion plaques and dense bodies
• Linkage: Dense bodies are connected to each other by intermediary filaments (e.g., desmin, vimentin).

Smooth muscle cells do not have sarcomeres.

Myofilament contraction and relaxation ^[1]

Excitation-contraction coupling

• Stimuli: control contraction and relaxation (differs from organ to organ)
  • Pacemaker cells (e.g., interstitial cells of Cajal produce rhythmic peristalsis in the gastrointestinal tract)
  • Mechanical stimuli (e.g., stretching)
  • Neurotransmitters of the autonomic nervous system (acetylcholine or noradrenaline) near smooth muscles
  • Metabolic stimuli (pH value, O₂)
  • Hormones; (e.g., NO, adrenaline, histamine, serotonin, oxytocin, vasopressin, vasoactive intestinal polypeptide)

Smooth muscle cells do not have motor endplates.

Steps of contraction

1. Stimulus opens L-type voltage-gated Ca²⁺ channels in the sarcolemma → influx of Ca²⁺ from the extracellular space into the smooth muscle cell (Ca²⁺ is also released from the SR, further increasing the intracellular concentration of Ca²⁺)
2. Ca²⁺ binds to calmodulin in the sarcoplasm, leading to activation of calmodulin.
3. Ca²⁺-calmodulin complex activates myosin light-chain kinase (MLCK).
4. MLCK phosphorylates the light chain head of the myosin filament.
5. ATPase activity in phosphorylated myosin enables crossbridge formation with actin, resulting in muscle contraction. (see “Crossbridge cycling” above)

The very slow attachment and detachment of crossbridges between actin and myosin allows smooth muscle to maintain prolonged tonic contraction while consuming little ATP and O₂.

The Ca²⁺ concentration determines the force of smooth muscle contraction: The higher the Ca²⁺ influx, the more force is generated.

Steps of relaxation

1. Stimuli
   • Neurotransmitters, inflammatory mediators, or drugs
     • Vascular endothelium
       • External binding of mediators (e.g., acetylcholine or bradykinin) to receptors → increased intracellular levels of Ca²⁺ → stimulation of endothelial nitric oxidase synthase (eNOS) → conversion of L-arginine to nitric oxide (NO) → increased levels of NO → passive diffusion of NO to adjacent smooth muscle cells of the blood vessel → NO stimulates the conversion of GTP to cGMP → activation of protein kinase G (PKG) → both cGMP and PKG activate MLCP
       • ACE inhibitors: increase bradykinin concentrations
     • Gastrointestinal tract: Tricyclic antidepressants, first-generation antipsychotics, and opioids inhibit the rhythmic contraction of smooth muscles (peristalsis), resulting in constipation and possibly paralytic ileus.
   • Reduced intracellular Ca²⁺ (due to activation of ion channels): Ca²⁺ ions are pumped into the extracellular space and partly into the SR by way of various transporters (e.g., Ca²⁺ ATPases, Na⁺/Ca²⁺ exchangers).
   • Hyperpolarization of the smooth muscle cell membrane (e.g., by the opening potassium channels) → prevented opening of stretch-activated Ca²⁺ channels → no further Ca²⁺ influx into the cell
2. Increased activity of myosin light-chain phosphatase (MLCP) and/or decreased MLCK activity
3. MLCP dephosphorylates myosin → myosin no longer interacts with actin → contraction ceases

The sliding of filaments and the cleavage of ATP by myosin ATPase occur 100–1,000 times slower in smooth muscle than in skeletal muscle. The maximal contraction speed of smooth muscles is therefore significantly lower than that of skeletal muscle.

MLCK phosphorylates myosin, leading to smooth muscle contraction. MLCP dephosphorylates myosin, leading to smooth muscle relaxation.

Smooth muscle cells Contract with Ca²⁺ and relax when there's NO stress.

Overview ^[1]

• Type: striated muscle tissue
• Location: : walls of the cardiac chambers (myocardium)
• Contraction regulation: under involuntary control of cardiac pacemaker cells and the autonomic nervous system
• Function: coordinated contraction of the heart

Microscopic anatomy ^[1]

• Structure
  • Branched mononuclear cells (central nucleus)
  • Contains many mitochondria
  • Cardiac syncytium: Individual cardiomyocytes are joined together via intercalated disks to form long fibers, which allows for rapid transmission of electrical impulses and coordinated contraction.
  • Sarcolemma invaginations: T-tubules
  • Sarcoplasmic reticulum: Ca²⁺ reservoir
• See “Cardiomyocytes.”

Myofilament arrangement ^[1]

• Thick filaments (myosin) and thin filaments (actin) are organized into sarcomeres.
• Myofilaments are anchored at the Z bands and the intercalated disks.
• Troponin and tropomyosin are regulatory proteins.

Myofilament contraction ^[1]

• Cardiac muscle contraction is similar to that of skeletal muscle, with a few minor differences.

Excitation-contraction coupling

• Site: pacemaker cells and myocardium
• Steps: AP originating from the cardiac pacemaker cells → muscle cell depolarization that diffuses across the sarcolemma and into T-tubules → short, rapid influx of sodium; prolonged Ca²⁺ influx (via L-type Ca²⁺ channels) → Ca²⁺-induced Ca²⁺ release from the SR → increased intracellular Ca²⁺

Contraction

• See “Crossbridge cycling”, above.

• Muscular conditions
  • Duchenne muscular dystrophy
  • Becker muscular dystrophy
  • Myotonic dystrophy type I
  • Myotonic dystrophy type II
  • Lambert Eaton syndrome
  • Myasthenia gravis
  • Myositis
• Autoimmune diseases
  • Polymyositis
  • Myasthenia gravis
• Neoplasms
  • Rhabdomyoma
  • Rhabdomyosarcoma
  • Angiomyolipoma
  • Leiomyoma
  • Leiomyosarcoma
  • Cancer cachexia
• Pharmacology
  • Botox
  • Skeletal muscle relaxants
  • Malignant hyperthermia (e.g., due to volatile anesthetics or succinylcholine) ^[9]
  • Vasodilating medications: dihydropyridines, hydralazine, nitrates, milrinone
• Neurological symptoms/examination
  • Dystonia
  • Myoclonus
  • Muscle power grading
  • Electromyography
• Miscellaneous
  • Rigor mortis
  • McArdle disease
  • Trichinellosis

1. Feher JJ. Quantitative Human Physiology. Academic Press ; 2017
2. Lapidos KA, Kakkar R, McNally EM. The dystrophin glycoprotein complex: signaling strength and integrity for the sarcolemma.. Circ Res. 2004; 94 (8): p.1023-31. doi: 10.1161/01.RES.0000126574.61061.25 . | Open in Read by QxMD
3. Herman DS, Lam L, Taylor MRG, et al. Truncations of Titin Causing Dilated Cardiomyopathy. N Engl J Med. 2012; 366 (7): p.619-628. doi: 10.1056/nejmoa1110186 . | Open in Read by QxMD
4. Catterall WA. Voltage-gated calcium channels. Cold Spring Harb Perspect Biol. 2011; 3 (8): p.a003947. doi: 10.1101/cshperspect.a003947 . | Open in Read by QxMD
5. Striessnig J, Bolz HJ, Koschak A. Channelopathies in Cav1.1, Cav1.3, and Cav1.4 voltage-gated L-type Ca2+ channels. Pflugers Arch. 2010; 460 (2): p.361-74. doi: 10.1007/s00424-010-0800-x . | Open in Read by QxMD
6. Al-Khayat HA. Three-dimensional structure of the human myosin thick filament: clinical implications.. Glob Cardiol Sci Pract. 2013; 2013 (3): p.280-302. doi: 10.5339/gcsp.2013.36 . | Open in Read by QxMD
7. Dayal A, Schrötter K, Pan Y, Föhr K, Melzer W, Grabner M. The Ca2+ influx through the mammalian skeletal muscle dihydropyridine receptor is irrelevant for muscle performance. Nat Commun. 2017; 8 (1). doi: 10.1038/s41467-017-00629-x . | Open in Read by QxMD
8. Squire JM. Muscle contraction: Sliding filament history, sarcomere dynamics and the two Huxleys.. Glob Cardiol Sci Pract.. 2016; 2016 (2): p.e201611. doi: 10.21542/gcsp.2016.11 . | Open in Read by QxMD
9. Cooke R. The Sliding Filament Model. J Gen Physiol. 2004; 123 (6): p.643-656. doi: 10.1085/jgp.200409089 . | Open in Read by QxMD