27 Cell Death Regulation in Muscle

1. INTRODUCTION TO MUSCLE

Skeletal muscle constitutes 40% of total body weight, and its primary function is to provide force and energy for locomotion, breathing, and postural support. It can also act as a source of heat production during coldinduced stress or exercise. Skeletal muscle is a highly adaptable tissue that exhibits a remarkable range of plasticity in response to different stimuli. It possesses distinctive structural and biochemical properties that distinguish it from all other tissues. There is a significant variation in size, type, and shape of skeletal muscles within the body. However, the underlying morphological structure remains the same. Common to all skeletal muscle is the presence of multiple myonuclei per cell, the innervation of several cells by single α-motor neurons, and the presence of ligaments and tendons.

As illustrated in Figure 27-1, numerous muscle fasciculi bundled together constitute the skeletal muscle. The muscle fasciculi are formed by a multitude of tightly bound individual muscle cells, or myofibers. Each myofiber consists of multiple myofibrils, which can be further subdivided into individual segments known as sarcomeres, the basic contractile unit of the muscle. Sarcomeres consist of thick (myosin) and thin (actin) filaments, arranged in a specific hexagonal ratio. Six actin filaments surround each myosin chain, and three myosin thick filaments border each actin molecule. A sarcomere is defined as the space between two neighboring Z-lines. The I-band, composed mainly of actin filaments, encompasses the Z-line and shortens during muscle contraction as the actin filaments slide over the myosin heavy chain. The A-band corresponds to the width of the myosin filaments and it remains static during muscle contraction. Sarcomeres arranged end to end

within each myofibril give skeletal muscle its unique striated appearance in electron micrographs.

Within each myofiber, the sarcoplasmic reticulum (SR) exists as a membranous network that surrounds every myofibril (Figure 27-1). The SR functions as a calcium (Ca2+ ) reservoir in skeletal muscle. During muscle contraction, an action potential travels down the invaginations of the plasma membrane known as t-tubules and induces Ca2+ release from the sarcoplasmic reticulum. Once released, Ca2+ binds to troponin and promotes a shift in the position of the inhibitory protein tropomyosin, which masks the myosin binding sites on the actin fibers. This allows for actin and myosin interaction and, consequently, muscle contraction as actin slides over the myosin molecules and the sarcomeres shorten in length.

Another important characteristic of skeletal muscle is that it houses two discrete pools of mitochondria (Figure 27-1). Mitochondria located beneath the sarcolemma of the muscle fiber are known as subsarcolemmal (SS) mitochondria, whereas those interspersed in between the myofibrils are called intermyofibrillar (IMF) mitochondria. The former comprise approximately 20% of the total mitochondrial volume and are mainly responsible for generating energy for membrane-bound functions. Conversely, IMF mitochondria account for the remaining 80% of the mitochondrial content and are presumably responsible for generating ATP for contractile purposes.

1.1. Skeletal muscle adaptation to endurance training

Skeletal muscle is a highly pliable tissue that can adapt phenotypically and metabolically to a range of

functional demands. One example of this adaptation is in response to repeated bouts of endurance exercise. This is referred to as endurance training, and it can involve modalities such as wheel or treadmill running or it can be imposed via chronic electrical stimulation. These paradigms induce changes in muscle oxidative phenotype and result in improved endurance performance. The transition toward a more oxidative phenotype with endurance training includes increases in expression of myoglobin, an enhanced rate of angiogenesis, a shift from type II toward type I myosin heavy chain expression, and an increase in mitochondrial biogenesis. A coordinated interplay between the nuclear and mitochondrial DNA regulates the process of mitochondrial biogenesis (Figure 27-1). Exercise stimulates signaling pathways that upregulate the transcription of several regulatory proteins. Peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α) has been referred to as the “master regulator” of mitochondrial biogenesis because of its role in the specific activation of nuclear genes encoding mitochondrial proteins. PGC-1α can bind to and activate the transcription of the nuclear respirator factor-1 (NRF-1) and NRF-2, two transcription factors that are responsible for expressing mitochondrial oxidative genes such as cytochrome c; proteins of the electron transport chain (ETC); mitochondrial import proteins; mitochondrial transcription factors Tfam, TFB1M, and TFB2M; and heme biosyntheses proteins. The mitochondrial-destined proteins interface with the protein import machinery that spans the outer and inner mitochondrial membranes to enter the mitochondria. In contrast to the nuclear genome, mito-

chondrial DNA (mtDNA) encodes only 13 proteins of the ETC, but the expression of each of these proteins is crucial for proper mitochondrial assembly and function. Tfam, TFB1M, and TFB2M regulate the transcription and translation of mtDNA-derived proteins, which act singularly, or in combination, with nuclear-encoded proteins to form multi-subunit complexes that are incorporated into the ETC.

1.2. Myonuclear domains

In addition to adaptations induced by endurance training, skeletal muscle can also respond to other physiologic perturbations, such as resistance exercise, muscle disuse, and injury/disease. In the case of a functional overload such as weight training, muscle hypertrophy is manifest. In contrast, muscle disuse is characterized by myofiber atrophy, whereas in response to injury, myofibers can repair themselves and regenerate. The growth and regenerative capacity of muscle is primarily mediated through muscle satellite cells. These cells occupy hollow dimples in the muscle fiber between the basal lamina and sarcolemma, and they are found in all vertebrates. Satellite cells are mononucleated progenitor cells that can be activated by exercise or injury-induced signals to give rise to myogenic precursor cells or myoblasts. During embryonic development, conditions of muscle regeneration, or muscle growth, satellite cells multiply, fuse, and donate their nuclei to the myofiber to induce muscle hypertrophy (Figure 27-2). Signals that mediate the fusion of myoblasts are largely dependent on the nuclear factor of