Muscle: Anatomy, Physiology, and Biochemistry

Key Points

  • The structure and function of skeletal muscle and its neural recruitment pattern can change rapidly in response to activity level (i.e., plasticity).

  • The smallest functional unit of muscle, the sarcomere, is composed of an almost crystalline array of filamentous proteins that convert metabolic energy into force and movement.

  • Muscles are attached to the skeleton through collagenous tendons.

  • Skeletal muscle contraction is controlled by the central nervous system through depolarization of specific efferent neurons called motor neurons.

  • Motor neurons innervate and depolarize muscle fibers through cholinergic synapses called neuromuscular junctions.

  • Afferent neurons provide the central nervous system with sensory information required for effective control of movement and posture.

  • Force is transmitted to the exterior through two sets of protein cell adhesion complexes: integrins and dystroglycans.


Approximately 660 skeletal muscles support and move the body under the control of the central nervous system (CNS). These muscles constitute up to 40% of adult human body mass. Most skeletal muscles are fastened by collagenous tendons across joints in the skeleton. The transduction of chemical energy into mechanical work by muscle cells leads to muscle shortening and consequent movement. A high degree of specialization in this tissue is evident from the intricate architecture and kinetics of intra-cellular membrane systems, the contractile proteins, and the molecular components that transmit force through the cell membrane to the extra-cellular matrix and tendons. Muscle cells normally exhibit wide variations in activity level and are able to adapt in size, isoenzyme composition, membrane organization, and energetics. In pathologic states, they often become deconditioned. These examples of plasticity can be surprisingly swift and extensive. This chapter outlines the structure and function of muscle and its relationship to associated connective tissue; this chapter will also introduce the basis for the highly adaptive response to altered functional demands and diseases.


Muscle Tissue

Parallel, aligned bundles of skeletal muscle fibers make up approximately 85% of the volume of muscle tissue and consist of a variety of signaling and contractile proteins ( Table 5.1 ). Nerves, blood supply, and connective tissue structures that provide support, elasticity, and force transmission to the skeleton (see later discussion) constitute the remaining volume. Muscle fibers range in length from a few millimeters to 30 cm; in diameter, they range from 10 to 500 μm. Muscle fibers have a typical length of 3 cm and diameter of 100 μm. This elongated shape is determined by the organization of the contractile proteins that occupy most of the sarcoplasm. Each muscle has a limited range of shortening that is amplified into large motions by lever systems of the skeleton, usually operating at a mechanical disadvantage. Variations in geometric arrangements of the fibers—parallel, convergent (fan-shaped), pennate (feather-like), sphincter (circular), or fusiform (thick in the middle with tapered ends)—determine some of the mechanical properties. For example, a muscle with fibers aligned parallel to the force-generating axis will have more basic contractile units (i.e., sarcomeres, as discussed later) in series than a similarly sized pennate muscle, thus allowing the parallel muscle to contract more quickly, but with less force than the pennate muscle. Muscles designed for strength (e.g., gastrocnemius) are typically pennate, whereas those designed for speed (e.g., biceps) tend to have parallel fibers. Muscles are commonly arranged around joints as antagonistic pairs facilitating bidirectional motion. When one muscle (the agonist) contracts, another (its antagonist) is relaxed and passively extended. Their roles reverse to actively generate the opposite motion, unless the action occurs passively by the force of gravity.


Signaling and Contractile Proteins of Skeletal Muscle

Protein Molecular Weight (kDa) Subunits (kDa) Location Function
Acetylcholine receptor 250 5 × 50 Postsynaptic membrane of neuromuscular junction Neuromuscular signal transmission
Annexins 38 F-actin–binding protein Membrane repair
Dihydropyridine receptor 380 1 × 160
1 × 130
1 × 60
1 × 30
T-tubule membrane Voltage sensor
Dysferlin 230 Periphery of myofibers Membrane repair
Ryanodine receptor 1800 4 × 450 Terminal cisternae of SR SR Ca 2+ release channel
Ca 2+ ATPase 110 Longitudinal SR Uptake of Ca 2+ into the SR
Calsequestrin 63 Lumen of SR terminal cisternae Binding and storage of Ca 2+
Troponin 70 1 × 18
1 × 21
1 × 31
Thin filament Regulation of contraction
Tropomyosin 70 2 × 35 Thin filament Regulation of contraction
Myosin 510 2 × 220
2 × 15
2 × 20
Thick filament Chemomechanical energy transduction
Actin 42 Thin filament Chemomechanical energy transduction
MM creatine phosphokinase 40 M line ATP buffer, structural protein
α-Actinin 190 2 × 95 Z line Structural protein
Titin 3000 From Z line to M line Structural protein
Nebulin 600 Thin filaments, in the I band Structural protein
Dystrophin 400 Sub-sarcolemma Structural integrity of sarcolemma

ATP, Adenosine triphosphate; ATPase, adenosine triphosphatase; SR, sarcoplasmic reticulum.

An extensive network of areolar connective tissue, forming the endomysium, surrounds each muscle fiber. Fine nerve branches and small capillaries, which are necessary for the exchange of nutrients and metabolic waste products, penetrate this layer. The endomysium is continuous with the perimysium, a connective tissue network that ensheathes the fasciculi (or small parallel bundles of muscle fibers), intrafusal fibers, larger nerves, and blood vessels. The epimysium encompasses the entire muscle. All three layers of connective tissue contain mostly types I, III, IV, and V collagen, with types IV and V predominating in the basement membranes surrounding each skeletal muscle fiber. The α1 2 α2-chain composition of the collagen IV isoform is the most prevalent and provides the mechanical stability and flexibility of the basil lamina. The perimysium and endomysium merge at the junction between muscle fibers and tendons, aponeuroses, and fasciae. These layers give the attachment sites great tensile strength and distribute axial force into shear forces over a larger surface area.

Fiber Types

Muscles adapt to their specific functions. In any given muscle, part of this adaptation arises from its composition and organization of fiber types. Human skeletal muscle fibers can be classified according to their myosin heavy chain (MHC) isoform (I, IIA, or IIX). MHC molecules break down adenosine triphosphate (ATP) to produce the energy necessary for muscle contraction. The rate of ATP breakdown, or the adenosine triphosphatase (ATPase) rate, of the MHC isoforms is I < IIA < IIX, leading to contractions that are relatively slow in MHC I fibers, fast in MHC IIA fibers, and very fast in MHC IIX fibers. ATP synthesis primarily occurs through aerobic respiration (i.e., oxygen is required) in MHC I (slow oxidative) fibers. ATP synthesis is aided by the nature of MHC I fibers in that they have more mitochondria, an increased capillary blood supply, and more myoglobin compared with MHC IIX (fast glycolytic) fibers, which use anaerobic respiration (i.e., oxygen is not required) to restore their ATP levels. MHC I fibers produce less power than MHC IIX fibers but are more resistant to fatigue. MHC IIA (fast oxidative-glycolytic) fibers can use both aerobic and anaerobic respiration and fall in between MHC I and IIX fibers in terms of mitochondria, blood supply, myoglobin, power output, and fatigability. Although most human skeletal muscles contain a mixture of fiber types, MHC I and IIA fibers are most prevalent, with pure MHC IIX fibers being relatively rare. Notably, individual fibers can contain a mixture of MHC isoforms, leading to six different fiber types in humans (“pure”: MHC I, IIA, and IIX; “mixed”: MHC I/IIA, IIA/IIX, and I/IIA/IIX), which allows for a wide range of contractile properties. A list of various attributes of MHC isoforms can be found in Table 5.2 .


Classification of Muscle Fiber Types by Myosin Heavy Chain Isoform

General Features MHC I MHC IIA MHC IIX
Mitochondria Many Intermediate Few
Capillary blood supply Extensive Moderate Moderate
SR membrane Sparse Extensive Extensive
Z line Wide Moderate Narrow
Protein Isoforms
Myosin essential light chain Slow and fast Fast Fast
Myosin regulatory light chain Slow and fast Fast Fast
Myosin binding protein–C Slow Fast Fast
Thin filament regulatory proteins Slow Fast Fast
Mechanical Properties
SR calcium ATPase rate Slow Fast Fast
Actomyosin ATPase rate Slow Fast Very fast
Contraction time Slow Fast Very fast
Shortening velocity Slow Fast Very fast
Power production Low Moderate High
Resistance to fatigue High Moderate Low
Metabolic Profile
Oxidative capacity High Moderate Low
Glycolytic capacity Moderate High High
Glycogen Low High High
Myoglobin High Moderate Low

ATPase, Adenosine triphosphatase; MHC, myosin heavy chain; SR, sarcoplasmic reticulum.

During development, fiber-type specificity may be partially determined before innervation. Although the biologic events and signals responsible for designating functional specialization in muscle fibers are not fully understood, classic cross-innervation experiments demonstrated that innervation can dynamically specify and modify the type of muscle fiber. After cross-innervation, the functional and histologic properties listed in Table 5.2 shift toward the target fiber type over a few weeks’ time, indicating the ability of muscles to adapt and remodel in accordance with the pattern of neuronal activity.

Events During Muscle Contraction

Neural Control

Voluntary control of muscle activation is a complex process. Afferent neurons emanating from sensory organs, such as cutaneous mechanoreceptors and thermoreceptors, pain receptors, joint receptors, and tendon organ and muscle spindles, provide the CNS with stimuli in the form of action potentials that, with or without additional stimuli from the brain, provide the necessary information for feedback control of effector organs via efferent neurons. Efferent neurons are specifically called motor neurons if their axons innervate muscle. Many times, more afferent than efferent neurons afford effective feedback control of movement and posture. The afferent and efferent neurons are accompanied by Schwann cells, which are glial cells residing in the peripheral nervous system. Neurons are termed myelinated if Schwann cells wrap around the axon at regularly spaced intervals. The points of bare axon between these Schwann cells are called nodes of Ranvier. Myelination enhances the velocity of action potential propagation by compelling a saltatory conduction of the action potential between neighboring nodes. Schwann cells may also fully, or nearly fully, cover the axon, thus rendering the neuron unmyelinated and relatively slow in action potential propagation. Three groups of myelinated motor neurons (α, β, and γ) are distinguished by diameter, propagation velocity, and target fiber type. Skeletal muscle fibers typically are innervated at several neuromuscular junctions along their length by branches of an α motoneuron (the largest and fastest) or a β motoneuron ( Fig. 5.1 ). Muscle spindles are innervated by β or γ motoneurons, in addition to the afferent system, for sensing muscle length and force. A single motor neuron and the muscle fibers it innervates constitute a motor unit. When a motor neuron is excited, all fibers in the motor unit are triggered to contract simultaneously. A motor unit responsible for fine movement contains few muscle fibers, but motor units for gross movement generally contain many fibers. The level of muscle activation is controlled from the CNS by the number of motor units recruited and the stimulus rate. Stimulus rate can be so infrequent as to elicit single muscle twitches, such as occur with the monosynaptic stretch reflex involving patellar tendon stretch and quadriceps activation. Conversely, the stimulus rate can be so frequent that individual twitches effectively fuse, causing nearly continuous activation of muscle force.

Fig. 5.1

Neuromuscular junction. (A) Scanning electron micrograph of an α motoneuron innervating several muscle fibers in its motor unit. Calibration bar = 10 μm. (B) Transmission electron micrograph. Calibration bar = 1 μm.

A, From Bloom W, Fawcett DW: A textbook of histology , ed 10. Philadelphia, WB Saunders, 1975. B, Courtesy Dr. Clara Franzini-Armstrong, University of Pennsylvania, Philadelphia.

Neuromuscular Transmission

At the neuromuscular junction, the axon tapers, loses its myelin sheath, and ends as a pre-synaptic terminal crowded with vesicles that contain the neurotransmitter acetylcholine. The postsynaptic membrane of the muscle is indented into folds that increase its surface area and the number of nicotinic acetylcholine receptors bound therein (see Fig. 5.1 ). The junctional cleft is a 20 to 40 nm-wide space between the pre-synaptic and postsynaptic membranes. When the motor neuron action potential reaches the pre-synaptic terminal, local voltage-gated Ca 2+ channels open and extra-cellular Ca 2+ streams into the terminal. Within milliseconds of Ca 2+ influx, the acetylcholine-loaded vesicles fuse with the pre-neurosynaptic membrane. Exocytosed acetylcholine rapidly diffuses across the junctional cleft and binds to the nicotinic acetylcholine receptors, which, in turn, open Na + and K + channels of the postneurosynaptic membrane. The membrane is locally depolarized, causing the initiation of an action potential which propagates along the muscle membrane (sarcolemma) at velocities up to 5 m/sec.

Excitation-Contraction Coupling

A network of tubules invaginate the sarcolemma and run deep into the muscle fiber. This transverse tubule network (T-tubules) pervades the fiber at regular intervals, coinciding with sarcomere boundaries along the length of the muscle, and surrounds the contractile apparatus with connected longitudinal and lateral segments ( Fig. 5.2 ). The lumen of this network is open to the extra-cellular space and contains high Na + and low K + concentrations of interstitial fluid. Action potentials at the surface membrane invade the entire T-tubular system. A specialized type of endoplasmic reticulum forms an entirely intra-cellular membrane system termed the sarcoplasmic reticulum (SR). Prevalent structures containing a T-tubule flanked by two terminal cisternae of the SR to form junctional complexes are termed triads (see Fig. 5.2 ). Terminal cisternae contain oligomers of the Ca 2+ -binding protein calsequestrin that provide the fiber with an internal reservoir of calcium ions. Ca 2+ channels, termed dihydropyridine receptors (DHPRs), are localized in the T-tubule membranes facing the cytoplasmic domain of SR Ca 2+ release channels, also called ryanodine receptors (RyRs), in the terminal cisternae membranes. These membrane proteins are further characterized in Table 5.1 .

Fig. 5.2

Membrane systems that relay the excitation signal from the sarcolemma to the cell interior. In the electron micrograph, two T-tubules are cut in cross-section. Electron densities spanning the gap between T-tubules and sarcoplasmic reticulum membranes are the ryanodine receptors, which are channels that release calcium into the myoplasm.

From Alberts B, Bray D, Lewish J, et al.: Molecular biology of the cell , ed 2. New York, Garland Publishers, 1989. Micrograph courtesy Dr. Clara Franzini-Armstrong, University of Pennsylvania, Philadelphia.

When an action potential depolarizes the T-tubular membrane, the DHPRs, primarily voltage sensors in skeletal muscle, transfer a signal from the T-tubules to the RyRs by direct interprotein coupling. Ca 2+ is then released cooperatively through the RyRs from the SR into the myoplasm, where it activates the contractile machinery. This sequence of events is termed excitation-contraction coupling.

Mutations in the α subunit of the DHPR in dysgenic mice lead to paralysis, because in these mutants, depolarization of the skeletal muscle membrane does not initiate release of Ca 2+ from the SR. Excitation-contraction coupling can be restored in cultured cells from these mice by transfection with complementary DNA encoding for the DHPR, and transfections using chimeric constructs have pinpointed the domain within the DHPR that specifies skeletal- or cardiac-type excitation-contraction coupling. Isoforms of the RyRs also help determine the characteristics of coupling between T-tubules and the SR. Channelopathies in human skeletal and heart muscle have been linked to DHPR mutations. Human malignant hyperthermia occurs in people with mutant RyRs that become trapped in the open state after exposure to halothane anesthetic agents.

Contractile Apparatus

The specific locations and functions of the contractile proteins are listed in Table 5.1 . Myofibrils ( Fig. 5.3D ) are long, 1 μm diameter cylindrical organelles that contain the contractile protein arrays responsible for work production, generation of force, and shortening. Each myofibril is a column of sarcomeres, the basic contractile units, that are approximately 2.5 μm in length and are delimited by Z lines ( Fig. 5.3D and E ) containing the densely packed structural protein α-actinin. The contractile and structural proteins within each sarcomere form a highly ordered, nearly crystalline lattice of interdigitating thick and thin myofilaments ( Fig. 5.3E, I, and J ). Myofilaments are remarkably uniform in both length and lateral registration, even during contraction, resulting in the cross-striated histologic appearance of skeletal and cardiac muscles. This highly periodic organization allows biophysical studies of muscle by sophisticated structural and spectroscopic techniques.

May 20, 2021 | Posted by in RHEUMATOLOGY | Comments Off on Muscle: Anatomy, Physiology, and Biochemistry

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