Physiology 500A

Lecture # 11

Dr. H. Rasgado-Flores

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GOOD TO EAT !

(Notice of a lecture on Muscle Presented by Professor D.R. Wilkie to the Institution of Electrical Engineers in London)

PURPOSE

1) To describe the cellular components of skeletal muscle

2) To describe the cellular and molecular processes of muscle contraction

3) To describe the basic mechanical variables in muscle contraction

4) To describe in the force-length relationship in isometric contractions

5) To describe the velocity-load relationship in isotonic contractions

I) INTRODUCTION

The ability to move is one of the fundamental characteristics of a living organism. Muscle contraction is an specialized example of this phenomenon. The main functions of skeletal muscle tissue are development of tension and shortening. The nervous system coordinates the activity of various muscles and of different parts of one or more muscles to produce useful movements and postures. The effect of muscle activity is transferred to the skeleton by means of tendons. The basis for movement is a biologic energy transformation called chemomechanical transduction. In this process most of the body's metabolic production of adenosine triphosphate (ATP) is converted into force or movement by muscle cells. For example, the musculature of an adult man in the resting state utilizes some 30 % of the total ATP energy generated by respiration. During very intense muscular activity, as in a sprint, the muscles consume 85% or more of the total ATP generated.

The performance of mechanical work is by no means limited to a few specialized tissues such as muscle. Actin and myosin are ubiquitous within eukaryotic cells. These proteins are involved in the movement of cells and the organelles within them. Indeed a striated muscle cell might be viewed as one end of a spectrum in which the myofibrils are relatively permanent structures, whereas in non-specialized cells the contractile components are assembled and dissolved as required. Evolution has led to specialization of muscle cells to minimize the ATP consumption required for specific functions.

It is constructive to consider why muscle, the striated variety in particular, has been such an appealing system for investigation. Firstly, a large proportion of the cell material is devoted to the contractile function. The two fundamental proteins involved, actin and myosin, comprise 80% of the structural proteins and are therefore available in large amounts for chemical characterization. Secondly, these proteins are arranged in a regular way which provides a clue to their mechanism of interaction. Thirdly, the contraction occurs on a macroscopic scale.

MUSCLE TYPES

Muscles have evolved to meet a variety of functions which demand gross differences in performance. Skeletal muscle may be required for short bursts of activity or prolonged contractions. Sustained activity is the hallmark of cardiac muscle which can function non-stop for over one hundred years. The flight muscles of a midge can contract one thousand times a second. A square centimeter of a molluscan adductor muscle can lift a 10 kg weight.

All muscles appear to involve interaction between actin- and myosin-containing filaments fuelled by ATP hydrolysis. However, the filaments may differ in their arrangement and in the protein isotypes they contain. Muscles also differ in the metabolic reactions they employ to generate ATP and in the way they are controlled by or respond to nerve impulses and chemical effectors. Traditionally muscles are classified in terms of their anatomy (striated vs. smooth). Both skeletal and cardiac muscle are called striated muscle because of a repetitive pattern of light and dark bands seen along the length of the muscle cells under the light microscope. Another distinction is made between voluntary muscles under conscious control and involuntary muscles in the internal organ system with autonomic innervation. However, the properties of different muscle cells are more readily understood in terms of their functional roles. A practical distinction between muscle cells is to separate them into attached to the skeleton and those in the walls of hollow organs.

Cells attached to a skeleton (these are all voluntary and striated) are often very long and bridge the attachment points of the muscle. The individual cells are anatomically and mechanically arranged in parallel. The cells function independently, and the total force produced by muscle equals the sum of the forces generated by its cells. Skeletal muscle cells are normally relaxed and are usually recruited to generate force and movement.

Muscle cells in the walls of hollow organs cannot function independently. In a continuous sheet of muscle, cells must be connected in series with each other as well as in parallel. Cells in hollow organs (typically involuntary and smooth) have two functional roles. They must be capable not only of generating force and movement, like skeletal muscle cells, but also of maintaining organ dimensions against applied loads. For example, vascular smooth muscle must bear the load imposed by the blood pressure to regulate blood flow.

II) STRUCTURE OF THE CONTRACTILE APPARATUS IN SKELETAL MUSCLE

Myofibers, Myofibrils, and Myofilaments

Skeletal muscle is composed of numerous parallel elongated cells referred to as muscle fibers or myofibers. These are about 10-100 m in diameter and vary with the length of the muscle, often extending its entire length. Under the electron microscope, the subcellular structure of the skeletal muscle fibers is composed of smaller fibrous structures 1 m in diameter, myofibrils which are separated by cytoplasm and arranged in parallel along the long axis of the cell (Figure 1). Each myofibril is further subdivided into thick and thin filaments. Thin filaments are about 7 nm wide and 1.0 m long, and thick filaments are about 10-14 nm wide (in mammals) and 1.6 m long. The arrangement of the thick and thin filaments produces the cross-striated appearance of the muscle, which results from a regular repetition of dense cross-bands (1.6 m in length) separated by less dense bands. The dense cross-bands, referred to as A bands because they are strongly anisotropic, contain the thick filaments arranged neatly in parallel. The less dense segments, the I bands, contain the thin filaments, which extend symmetrically in opposite directions from a dense thin line, the Z line. The term I band is based on the fact that this zone is highly isotropic.

The Z line structure contributes toward keeping the thin filaments arranged in register and with a regular spacing. The gap between the terminations of the thin filaments is called the H zone, and the darker area in the center of the H zone is called the M line (Figure 1).

Figure 1. Structure of skeletal muscle. a, Whole muscle. b, Muscle fibers. c, Schematic representation of the three-dimensional relationships between membrane elements of a skeletal muscle fiber.

Sarcomere

The sarcomere is the fundamental contractile unit of the muscle. It consists of the region between two consecutive Z lines; thus, this unit consists of one A band and two half I bands at each extreme of the sarcomere. Its length at rest varies between 2.0 and 2.6 m.

Table I summarizes the effect of muscle shortening and elongation on the size of the various muscle bands.

In accord with the above considerations, the microscopic pattern seen in cross-sections of muscle fibers depend on the level of the section (Figure 2). Near the Z line, only thin filaments are observed, whereas at the site of overlap of thick and thin filaments, each filament is surrounded by six thin filaments and each thin filament by three thick filaments. A cross section through the M line shows the thin connections between adjoining thick filaments.

Figure 2. Longitudinal (top) and cross-sectional (bottom) diagrams showing the relationships between thick and thin filaments of a sarcomere.

Sarcolemma

The sarcolemma is the outer membrane surrounding each muscle fiber. The main function of the sarcolemma in muscle contraction is to conduct the wave of depolarization originating at the motor end-plate over the entire cell surface to initiate contraction.

Tubular extensions of the sarcolemma, called T (transverse)-tubules (Figure 1), extend deep into the fiber at the level of either the Z line or at the junction of the A-I bands, depending on the type of muscle. The T-tubules, about 0.03 m in diameter, allow a wave of depolarization traveling along the sarcolemma during muscle excitation to pass rapidly into the fiber so that deep lying myofibrils may be rapidly activated.

Sarcoplasm

The sarcoplasm of a muscle fiber consists of the contents of the sarcolemma, excluding the proteins of the contractile elements and nuclei. It contains the usual cytoplasmic organelles including mitochondria, sarcoplasmic reticulum, and Golgi apparatus.

Sarcoplasmic Reticulum

The sarcoplasmic reticulum (SR) is an elaborately anastomosing tubular network which surrounds the myofibrils and runs parallel to the myofilaments (Figure 1). The SR tubules may extend the full length of the sarcomere and end in dilated structures called terminal cisternae, which lie on opposite sites of the T-tubules. The SR can thus be divided into the longitudinal SR and the terminal cisternae. A group of one T-tubule and two terminal cisternae is called a triad. Densities called "feet" are located in the narrow space between the terminal cisternae and the T tubules (Figure 3).

The functions of the SR are the release of calcium (Ca2+) during muscle contraction and the sequestration and storage of Ca2+ during muscle relaxation.

Figure 3. Electron micrograph of a longitudinal section of a muscle fiber showing a triad at the level of the Z lie. Two "feet" are visible on each side of the T-tubule.

Nuclei

Skeletal muscle fibers are multinucleated. The nuclei are located in the periphery.

III) PROTEINS OF THE CONTRACTILE ELEMENTS

Thin Filaments

Thin filaments are composed primarily of three types of protein: actin, tropomyosin and troponin in a ratio of 7:1:1.

ACTIN

Actin is a monomeric globular protein with a molecular weight of 42,000 and a diameter of 4-5 nm. Each monomer contains binding sites for other actin monomers, myosin, tropomyosin, troponin, ATP, and cations. Under conditions existing in the cytoplasm it polymerizes to form twisted, two stranded filaments (Figure 4).

Figure 4. Composition and structure of thin filaments in muscle. Globular actin monomers (top) polymerize into a two-stranded helical filament. The thin filament structure is completed with the addition of stiff, rod-shaped tropomyosin molecules. Troponin (black rectangles) is a regulatory protein bound to the tropomyosin component of the thin filament in vertebrate striated muscles (bottom). For clarity the tropomyosin-troponin complexes associated with only one strand of the actin helix are illustrated. Thin filaments are anchored to Z disks in striated muscles. Filaments on each side of a Z disk have opposite polarities.

TROPOMYOSIN

Tropomyosin is a rod-shaped protein which consists of two -helical chains, each with a molecular weight of approximately 35,000, wound around each other to form a coiled coil. Each molecule of tropomyosin is associated with six or seven actins in one strand.

TROPONIN

Troponin consists of a complex of three separate proteins: Troponin-T, troponin-C, and troponin-I. Each troponin complex is bound to a tropomyosin molecule.

While only actin and myosin are directly involved in tension generation, the tropomyosin and troponin complex regulate the actin-myosin interaction, hence are called regulatory proteins.

Thick Filaments

MYOSIN

Myosin is a dimer with a molecular weight of 470,000. It consists of two globular heads, which hydrolyze ATP and interact with actin, and a rod-like region, which confers stability to the molecule. The myosin molecule contains six different polypeptides. These peptides are not covalently linked and can be dissociated by detergents or denaturating agents and are separated into three pairs: one set of large heavy chains and two sets of light chains. Most of the heavy chain has an -helical structure, and the two strands are twisted around each other in a supercoil that forms a long, rigid, insoluble "tail". Each end of the heavy chains has a globular tertiary structure (head). Thus each myosin molecule has two heads to one end of the long tail.

Myosin molecules will aggregate in a particular pattern to form filaments, similar to the thick filaments seen in intact muscle. The myosin molecules aggregate with their globular ends directed toward the ends of the filaments (Figure 5).