골격근의 기원, 변화, 재생에 관한 이야기

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근골격계 근육의 Genesis, modulation, regeneration에 대한 이야기

The term “muscle” includes many cell types, all specialized for contraction but in other respects dissimilar. As noted in Chapter 16, all eucaryotic cells possess a contractile system involving actin and myosin, but muscle cells have developed this apparatus to a high degree. Mammals possess four main categories of cells specialized for contraction: skeletal muscle cells, heart (cardiac) muscle cells, smooth muscle cells, and myoepithelial cells (Figure 23–47). 

Figure 23–47 The four classes of muscle cells of a mammal. (A) Schematic drawings (to scale). (B–E) Scanning electron micrographs, showing (B) skeletal muscle from the neck of a hamster, (C) heart muscle from a rat, (D) smooth muscle from the urinary bladder of a guinea pig, and (E) myoepithelial cells in a secretory alveolus from a lactating rat mammary

gland. The arrows in (C) point to intercalated discs—end-to-end junctions between the heart muscle cells; skeletal

muscle cells in long muscles are joined end to end in a similar way. Note that the smooth muscle is shown at a lower

magnification than the others. (B, courtesy of Junzo Desaki; C, from T. Fujiwara, in Cardiac Muscle in Handbook of Microscopic Anatomy [E.D. Canal, ed.]. Berlin: Springer-Verlag, 1986; D, courtesy of Satoshi Nakasiro; E, from T. Nagato et al., Cell Tiss. Res. 209:1–10, 1980. With permission from Springer-Verlag.)

These differ in function, structure, and development. Although all of them generate contractile forces by using organized filament systems based on actin and myosin, the actin and myosin molecules employed have somewhat different amino acid sequences, are differently arranged in the cell, and are associated with different sets of proteins to control contraction. Skeletal muscle cells are responsible for practically all movements that are under voluntary control. These cells can be very large (2–3 cm long and 100 mm in diameter in an adult human) and are often called muscle fibers because of their highly elongated shape. Each one is a syncytium, containing many nuclei within a common cytoplasm. The other types of muscle cells are more conventional, generally having only a single nucleus. Heart muscle cells resemble

skeletal muscle fibers in that their actin and myosin filaments are aligned in very

orderly arrays to form a series of contractile units called sarcomeres, so that the

cells have a striated (striped) appearance. Smooth muscle cells are so named

because they do not appear striated. The functions of smooth muscle vary

greatly, from propelling food along the digestive tract to erecting hairs in

response to cold or fear. Myoepithelial cells also have no striations, but unlike

all other muscle cells they lie in epithelia and are derived from the ectoderm.

They form the dilator muscle of the eye’s iris and serve to expel saliva, sweat, and

milk from the corresponding glands, as discussed earlier (see Figure 23–11). The

four main categories of muscle cells can be further divided into distinctive subtypes,

each with its own characteristic features.

The mechanisms of muscle contraction are discussed in Chapter 16. Here we consider how muscle tissue is generated and maintained. We focus on the skeletal muscle fiber, which has a curious mode of development, a striking ability to modulate its differentiated character, and an unusual strategy for repair.

Myoblasts Fuse to Form New Skeletal Muscle Fibers

Chapter 22 described how certain cells, originating from the somites of a vertebrate embryo at a very early stage, become determined as myoblasts, the precursors of skeletal muscle fibers. The commitment to be a myoblast depends on

gene regulatory proteins of at least two families—a pair of homeodomain proteins called Pax3 and Pax7, and the MyoD family of basic helix–loop–helix proteins (discussed in Chapter 7). These act in combination to give the myoblast a

memory of its committed state, and, eventually, to regulate the expression‎ of other genes that give the mature muscle cell its specialized character (see Figure 7–75). After a period of proliferation, the myoblasts undergo a dramatic change

of state: they stop dividing, switch on the expression‎ of a whole battery of muscle- specific genes required for terminal differentiation, and fuse with one another to form multinucleate skeletal muscle fibers (Figure 23–48). 

Figure 23–48 Myoblast fusion in culture. The culture is stained with a fluorescent antibody (green) against skeletal muscle myosin, which marks differentiated muscle cells, and with a DNA-specific dye (blue) to show cell nuclei. (A) A short time after a change to a culture medium that favors differentiation, just two of the many myoblasts in the field of view have switched on myosin production and have fused to form a muscle cell with two nuclei (upper right). (B) Somewhat later, almost all the cells have differentiated and fused. (C) High-magnification view, showing characteristic striations (fine

transverse stripes) in two of the multinucleate muscle cells. (Courtesy of Jacqueline Gross and Terence Partridge.)

Fusion involves specific cell–cell adhesion molecules that mediate recognition between newly differentiating myoblasts and fibers. Once differentiation has occurred, the cells do not divide and the nuclei never again replicate their DNA. Myoblasts that have been kept proliferating in culture for as long as two years still retain the ability to differentiate and can fuse to form muscle cells in response to a suitable change in culture conditions. Appropriate signal proteins such as fibroblast or hepatocyte growth factor (FGF or HGF) in the culture medium can maintain myoblasts in the proliferative, undifferentiated state: if these soluble factors are removed, the cells rapidly stop dividing, differentiate, and fuse. The system of controls is complex, however, and attachment to the extracellular matrix is also important for myoblast differentiation. Moreover, the process of differentiation is cooperative: differentiating myoblasts secrete factors that apparently encourage other myoblasts to differentiate.

Muscle Cells Can Vary Their Properties by Changing the Protein  Isoforms They Contain

Once formed, a skeletal muscle fiber grows, matures, and modulates its character.

The genome contains multiple variant copies of the genes encoding many of

the characteristic proteins of the skeletal muscle cell, and the RNA transcripts of

many of these genes can be spliced in several ways. As a result, muscle fibers

produce many variant forms (isoforms) of the proteins of the contractile apparatus.

As the muscle fiber matures, it synthesizes different isoforms, satisfying

the changing demands for speed, strength, and endurance in the fetus, the newborn,

and the adult. Within a single adult muscle, several distinct types of skeletal

muscle fibers, each with different sets of protein isoforms and different functional

properties, can be found side by side (Figure 23–49). The characteristics

of the different fiber types are determined partly before birth by the genetic program

of development, partly in later life by activity and training. Different

classes of motor neurons innervate slow muscle fibers (for sustained contraction)

and fast muscle fibers (for rapid twitch), and the innervation can regulate

muscle-fiber gene expression‎ and size through the different patterns of electrical

stimulation that these neurons deliver.

Skeletal Muscle Fibers Secrete Myostatin to Limit Their Own Growth

A muscle can grow in three ways: its fibers can increase in number, in length, or

in girth. Because skeletal muscle fibers are unable to divide, more of them can

be made only by the fusion of myoblasts, and the adult number of multinucleated

skeletal muscle fibers is in fact attained early—before birth, in humans.

Once formed, a skeletal muscle fiber generally survives for the entire lifetime of

the animal. However, individual muscle nuclei can be added or lost. The enormous

postnatal increase in muscle bulk is achieved by cell enlargement. Growth

in length depends on recruitment of more myoblasts into the existing multinucleated

fibers, which increases the number of nuclei in each cell. Growth in

girth, such as occurs in the muscles of weightlifters, involves both myoblast

recruitment and an increase in the size and numbers of the contractile myofibrils

that each muscle fiber nucleus supports. What, then, are the mechanisms that control muscle cell numbers and muscle

cell size? One part of the answer lies in an extracellular signal protein called

myostatin. Mice with a loss-of-function mutation in the myostatin gene have

enormous muscles—two to three times larger than normal (Figure 23–50). 

Both the numbers and the size of the muscle cells seem to be increased. Mutations in

the same gene are present in so-called “double-muscled” breeds of cattle (see

Figure 17–69): in selecting for big muscles, cattle breeders have unwittingly

selected for myostatin deficiency. Myostatin belongs to the TGFb superfamily of

signal proteins. It is normally made and secreted by skeletal muscle cells, and it

acts powerfully on myoblasts, inhibiting both proliferation and differentiation.

Its function, evidently, is to provide negative feedback to limit muscle growth, in

adult life as well as during development. The growth of some other organs is

similarly controlled by a negative-feedback action of a factor that they themselves

produce. We shall encounter another example in a later section.

Some Myoblasts Persist as Quiescent Stem Cells in the Adult

Even though humans do not normally generate new skeletal muscle fibers in

adult life, they still have the capacity to do so, and existing muscle fibers can

resume growth when the need arises. Cells capable of serving as myoblasts are

retained as small, flattened, and inactive cells lying in close contact with the

mature muscle cell and contained within its sheath of basal lamina (Figure

23–51). If the muscle is damaged or stimulated to grow, these satellite cells are

activated to proliferate, and their progeny can fuse to repair the damaged muscle

or to allow muscle growth. Like myoblasts, they are regulated by myostatin.

Satellite cells, or some subset of the satellite cells, are thus the stem cells of

adult skeletal muscle, normally held in reserve in a quiescent state but available

when needed as a self-renewing source of terminally differentiated cells. Studies

of these cells have provided some of the clearest evidence for the immortal

strand hypothesis of asymmetric stem-cell division, as illustrated earlier in Figure

23–10).

The process of muscle repair by means of satellite cells is, nevertheless, limited

in what it can achieve. In one form of muscular dystrophy, for example, a

genetic defect in the cytoskeletal protein dystrophin damages differentiated

skeletal muscle cells. As a result, satellite cells proliferate to repair the damaged

muscle fibers. This regenerative response is, however, unable to keep pace with

the damage, and connective tissue eventually replaces the muscle cells, blocking

any further possibility of regeneration. A similar loss of capacity for repair

seems to contribute to the weakening of muscle in the elderly.

In muscular dystrophy, where the satellite cells are constantly called upon to

proliferate, their capacity to divide may become exhausted as a result of progressive

shortening of their telomeres in the course of each cell cycle (discussed

in Chapter 17). Stem cells of other tissues seem to be limited in the same way, as

we noted earlier in the case of hemopoietic stem cells: they normally divide only

at a slow rate, and mutations or exceptional circumstances that cause them to

divide more rapidly can lead to premature exhaustion of the stem-cell supply. 

Summary

Skeletal muscle fibers are one of four main categories of vertebrate cells specialized for contraction, and they are responsible for all voluntary movement. Each skeletal musclefiber is a syncytium and develops by the fusion of many myoblasts.Myoblasts proliferate extensively, but once they have fused, they can no longer divide. Fusion generally follows the onset of myoblast differentiation, in which many genes encoding muscle-specific proteins are switched on coordinately. Some myoblasts persist in a quiescent state as satellite cells in adult muscle; when a muscle is damaged, these cells are reactivated to proliferate and to fuse to replace the muscle cells that have been lost. They are the stem cells of skeletal muscle. Muscle bulk is regulated homeostatically by a negative-feedback mechanism, in which existing muscle secretes myostatin, which inhibits further muscle growth.