《医学生理学 Medical Physiology》参考教材资料（PDF电子书籍）Uwe Ackermann. PDQ Physiology, 2002, Uwe Ackerman

Chapter 1 General Physiologic Processes 35 APOPTOSIS poptosis is orderly, programmed cell death. It differs from necrosis, in part by the complex involvement of extracellular signals and intracellular sec- ond messenger cascades and in part by its lack of phagocytic or other anti- genic involvement. Cells that have undergone apoptosis leave behind no debris and activate no inflammatory response. A normal living cell exists in a state of balance between proapoptotic and antiapoptotic survival factors. Among the proapoptotic influences are(1) DNA damage with subsequent activation of p53,(2)activation of a variety of receptors for apoptotic triggers like tumor necrosis factor-alpha(TFN-a) and(3)a variety of environmental insults, such as hypoxia. The pathways leading to apoptosis are complex and include at least two common features. The first is activation of a family of cytoplasmic proteases, called caspases, nd the second is the distinctive degradation of nuclear DNA

APOPTOSIS Apoptosis is orderly, programmed cell death. It differs from necrosis, in part by the complex involvement of extracellular signals and intracellular sec￾ond messenger cascades and in part by its lack of phagocytic or other anti￾genic involvement. Cells that have undergone apoptosis leave behind no debris and activate no inflammatory response. A normal living cell exists in a state of balance between proapoptotic and antiapoptotic survival factors. Among the proapoptotic influences are (1) DNA damage with subsequent activation of p53, (2) activation of a variety of receptors for apoptotic triggers like tumor necrosis factor-alpha (TFN-α), and (3) a variety of environmental insults, such as hypoxia. The pathways leading to apoptosis are complex and include at least two common features. The first is activation of a family of cytoplasmic proteases, called caspases, and the second is the distinctive degradation of nuclear DNA. Chapter 1 General Physiologic Processes 35

Muscle Muscle is excitable, contractile tissue It is classified. on the basis of its microscopic appearance, as striated muscle or smooth muscle. This difference arises from the different physical arrangements of the con- tractile proteins. STRIATED MUSCLE Striated muscle is further divided into skeletal muscle and cardiac muscle Skeletal muscle typically bridges two attachment points on the skeleton and is in a relaxed state. unless there is a need for motion of one attach ment point relative to the other. Cardiac muscle is arranged so as to form a hollow bag, suspended from a fibrous ring. It contracts and relaxes throughout life and at a rate between 35 and 200 beats per minute. morphology of Striated Muscle A muscle consists of several muscle columns. Each column consists of sev ral muscle fibers(Figure 2-1), and each fiber consists of several myofibrils, each 1 to 2 um in diameter. Myofibrils clearly show repeating motifs of light and dark bands, bounded at intervals of about 2 um by narrow, dark band called the Z-lines. A typical cell incorporates several myofibrils, Z-lines, and nuclei and is bounded by an external membrane, called the sarcolemma The sarcolemma is the plasma membrane of muscle cells. It penetrat deeply into each cell by the system of transverse tubules(T-tubules). In skele This section will focus on skeletal muscle. The morphology of cardiac muscle is described in Chapter 6, Cardiovascular Physiology

Muscle Muscle is excitable, contractile tissue. It is classified, on the basis of its microscopic appearance, as striated muscle or smooth muscle. This difference arises from the different physical arrangements of the con￾tractile proteins. STRIATED MUSCLE Striated muscle is further divided into skeletal muscle and cardiac muscle. • Skeletal muscle typically bridges two attachment points on the skeleton and is in a relaxed state, unless there is a need for motion of one attach￾ment point relative to the other. • Cardiac muscle is arranged so as to form a hollow bag, suspended from a fibrous ring. It contracts and relaxes throughout life and at a rate between 35 and 200 beats per minute. Morphology of Striated Muscle A muscle consists of several muscle columns.* Each column consists of sev￾eral muscle fibers (Figure 2–1), and each fiber consists of several myofibrils, each 1 to 2 µm in diameter. Myofibrils clearly show repeating motifs of light and dark bands, bounded at intervals of about 2 µm by narrow, dark bands called the Z-lines. A typical cell incorporates several myofibrils, Z-lines, and nuclei and is bounded by an external membrane, called the sarcolemma. Sarcolemma The sarcolemma is the plasma membrane of muscle cells. It penetrates deeply into each cell by the system of transverse tubules (T-tubules). In skele- 2 36 *This section will focus on skeletal muscle. The morphology of cardiac muscle is described in Chapter 6, “Cardiovascular Physiology

Chapter 2 Muscle Bone Muscle columns Muscle fiber Myofibrils 0 igure 2-1 Skeletal muscle is organized into columns, fibers, and myofibrils. Z= the Z-line (or Z-disk) formed by a-actinin, an actin- binding protein. tal muscle, each T-tubule occurs where the a and i bands join( Figure 2-2) In cardiac muscle, they occur at each Z-line. These tubular invaginations(1) allow extracellular fluid to be in close proximity to the cell interior and(2) bring the sarcolemma into close proximity with the endoplasmic reticulum, which is called the sarcoplasmic reticulum(SR) in muscle cells. Sarcoplasmic Reticulum This membrane-lined structure has evolved as a region specialized for uptake, storage, and triggered release of Ca++. Its longitudinal elements are aligned with the long axis of muscle fibers and are rich in proteins that pump or store Ca*. Near the T-tubules, the slender longitudinal channels broaden to form the cisternae that surround the T-tubules. These regions are rich in proteins that act as Cat*+ release channels. Sarcomere The sarcomere is the contractile unit. It is bounded by two neighboring Z- lines(see Figure 2-2)and contains three types of proteins that are special ized, respectively, for structure, contraction, and regulation of contraction

tal muscle, each T-tubule occurs where the A and I bands join (Figure 2–2). In cardiac muscle, they occur at each Z-line. These tubular invaginations (1) allow extracellular fluid to be in close proximity to the cell interior and (2) bring the sarcolemma into close proximity with the endoplasmic reticulum, which is called the sarcoplasmic reticulum (SR) in muscle cells. Sarcoplasmic Reticulum This membrane-lined structure has evolved as a region specialized for uptake, storage, and triggered release of Ca++. Its longitudinal elements are aligned with the long axis of muscle fibers and are rich in proteins that pump or store Ca++. Near the T-tubules, the slender longitudinal channels broaden to form the cisternae that surround the T-tubules. These regions are rich in proteins that act as Ca++ release channels. Sarcomere The sarcomere is the contractile unit. It is bounded by two neighboring Z￾lines (see Figure 2–2) and contains three types of proteins that are special￾ized, respectively, for structure, contraction, and regulation of contraction. Chapter 2 Muscle 37 Bone Bone Muscle fibers Muscle columns Myofibrils Z Z Z Figure 2–1 Skeletal muscle is organized into columns, fibers, and myofibrils. Z = the Z-line (or Z-disk) formed by α-actinin, an actin-binding protein

PDQ PHYSIOLOGY yasIn Actin Titin 这 M-line Z-line Z-line H-zone I-band A-band Figure 2-2 Ultrastructure of the striated muscle sarcomere. It is bounded by two Z-lines and is formed by thin filaments that contain mostly actin, the structural protein titin, and thick fila ments that are formed mostly by myosin Structural proteins. Approximately 10% of the myofibril mass is the giant protein, titin. It is important for both structural integrity and the passive tension response of a stretched muscle fiber. Single titin molecules are more than 1 um long and span from the Z-line to the M-line(see Figure 2-2) In the A-band, titin provides regularly spaced binding sites for other A band proteins, such as light meromyosin(LMM) and C protein. The I- band region of titin is extensible and is the major contributor to the passive tension that is seen when relaxed muscle is stretched Contractile proteins. The thin and thick filaments of striated muscle are formed mostly and respectively by the proteins actin and myosin. They are called the contractile proteins because they will, when combined in tro, form gel-like threads that contract when adenosine triphosphate (ATP)is added Actin. Actin is the major component of the thin filament(see Figure 2-2) It exists as F-actin, two slowly twisting strands of actin monomers with crossovers spaced about 36 nm at intervals of 6.5 G-actin monomers Figure 2-3). G-actin molecules have a single polypeptide chain of 375

Structural proteins. Approximately 10% of the myofibril mass is the giant protein, titin. It is important for both structural integrity and the passive tension response of a stretched muscle fiber. Single titin molecules are more than 1 µm long and span from the Z-line to the M-line (see Figure 2–2). In the A-band, titin provides regularly spaced binding sites for other A￾band proteins, such as light meromyosin (LMM) and C protein. The I￾band region of titin is extensible and is the major contributor to the passive tension that is seen when relaxed muscle is stretched. Contractile proteins. The thin and thick filaments of striated muscle are formed mostly and respectively by the proteins actin and myosin. They are called the contractile proteins because they will, when combined in vitro, form gel-like threads that contract when adenosine triphosphate (ATP) is added. Actin. Actin is the major component of the thin filament (see Figure 2–2). It exists as F-actin, two slowly twisting strands of actin monomers with crossovers spaced about 36 nm at intervals of 6.5 G-actin monomers (Figure 2–3). G-actin molecules have a single polypeptide chain of 375 38 PDQ PHYSIOLOGY Z-line Z-line Actin Myosin Titin I - band I - band A - band H - zone M - line Figure 2–2 Ultrastructure of the striated muscle sarcomere. It is bounded by two Z-lines and is formed by thin filaments that contain mostly actin, the structural protein titin, and thick fila￾ments that are formed mostly by myosin

hapter 2 Muscle in C A)weak binding Actin Figure 2-3 Ultrastructure of the thin filament in relaxed and activated states A, End view of a thin filament in the resting state. Two actin monomers joined by pling subdomains. Tropomyosin is in a bloc blocked or only weakly attached by electrostatic forces between the positively charged myosin essential light chain and negatively charged residues within the c-terminal portion B,. Side view of the thin filament in the resting state. The myosin head has been omitted for of Tn-l.(2)Tn- attaches by its N-terminal to both the c-terminal of Tn-c and the c-terminal of Tn-t(colored circle). the tral spiral of Tn- is attached by its ATPase-inhibitory domain to actin (indicated in color. (3)Tn is attached by its C-terminal to the N-terminal of Tn-I, by its midregion to tropomyosin, and by its N-terminal to the head-tail junction of adjacent tropomyosin molecules C, The activated state. Strong force-generating actomyosin cross-bridges are formed when opomyosin has moved from a blocking position toward the groove formed by the intertwined actin strands D, Side view of the thin filament in the cocked and"on"states( with myosin omitted for clar- has triggered several Ca**-sensitive detachments and attachments. (1)Tn-C remains attached to the N-terminal of In-l but is also attached by its n-terminal to the central ral of Tn-l. Furthermore, the linker region of Tn-C is attached to the C-terminal of Tn-T(indi- cated by colored circle). (2)Tn-I is attached by both its central spiral (colored spheres) and its N-terminal to Tn-C. The N-terminal of Tn-I is attached to tropomyosin(colored circle, and Tn I binding to actin has been broken. (3) The binding of the In-T C-terminal midregion to and this has allowed tropomyosin to move from its resting posi- tion (indicated by dashed lines by 1 or 2 nm toward the actin groove. These changes in con- rmation and state of the thin filament proteins permit myosin S, heads to form hydrolyzed to provide energy. (4) Removal of the Tn-I inhibitory domains from the actin allows weakly bound actomyosin cross-bridges to convert to a force-generating state suggests that only th spanned by one olecule are released from inhibition by one Ca*+ ically coupled to adjacent tropomyosins and their actin molecules tide ch s: Tn-C=troponin C: Tn-I=troponin 1: Tn-T=troponin T: N= NH2 terminus of polypep-

Chapter 2 Muscle 39 N N C C Ca++ binding site Troponin T Troponin I Troponin C Tropomyosin A) B) C) D) Tropomyosin Actin S1 Weak binding Figure 2–3 Ultrastructure of the thin filament in relaxed and activated states. A, End view of a thin filament in the resting state. Two actin monomers joined by their cou￾pling subdomains. Tropomyosin is in a blocking position where myosin S1 heads are either blocked or only weakly attached by electrostatic forces between the positively charged myosin essential light chain and negatively charged residues within the C-terminal portion of actin. B, Side view of the thin filament in the resting state. The myosin head has been omitted for clarity. (1) Tn-C is attached by its C-terminal to the N-terminal of Tn-I. (2) Tn-I attaches by its N-terminal to both the C-terminal of Tn-C and the C-terminal of Tn-T (colored circle). The cen￾tral spiral of Tn-I is attached by its ATPase-inhibitory domain to actin (indicated in color). (3) Tn￾T is attached by its C-terminal to the N-terminal of Tn-I, by its midregion to tropomyosin, and by its N-terminal to the head-tail junction of adjacent tropomyosin molecules. C, The activated state. Strong, force-generating actomyosin cross-bridges are formed when tropomyosin has moved from a blocking position toward the groove formed by the intertwined actin strands. D, Side view of the thin filament in the cocked and “on” states (with myosin omitted for clar￾ity). Transition from the “off” state begins when Ca++ has bound to the N-terminal of Tn-C and has triggered several Ca++-sensitive detachments and attachments. (1) Tn-C remains attached by its C-terminal to the N-terminal of Tn-I but is also attached by its N-terminal to the central spiral of Tn-I. Furthermore, the linker region of Tn-C is attached to the C-terminal of Tn-T (indi￾cated by colored circle). (2) Tn-I is attached by both its central spiral (colored spheres) and its N-terminal to Tn-C. The N-terminal of Tn-I is attached to tropomyosin (colored circle), and Tn￾I binding to actin has been broken. (3) The binding of the Tn-T C-terminal midregion to tropomyosin has weakened, and this has allowed tropomyosin to move from its resting posi￾tion (indicated by dashed lines) by 1 or 2 nm toward the actin groove. These changes in con￾formation and state of the thin filament proteins permit myosin S1 heads to form actomyosin complexes that are capable of generating force provided that ATP is present and can be hydrolyzed to provide energy. (4) Removal of the Tn-I inhibitory domains from the proximity of actin allows weakly bound actomyosin cross-bridges to convert to a force-generating state. Although the diagram suggests that only the seven actin molecules spanned by one tropomyosin molecule are released from inhibition by one Ca++, the effect of that one Ca++ may be mechan￾ically coupled to adjacent tropomyosins and their associated G-actin molecules. C = COOH terminus; Tn-C = troponin C; Tn-I = troponin I; Tn-T = troponin T; N = NH2 terminus of polypep￾tide chain