Which of the following terms describe skeletal muscle?

Abstract

Skeletal muscle is a highly malleable tissue that is a central factor in whole-body health and the maintenance of energy homeostasis. Skeletal muscle accounts for approximately 45–50% of body mass and plays a fundamental role in locomotion, oxygen (O2) consumption, energy metabolism, and substrate turnover and storage. This article will primarily focus on recent research pertaining to skeletal muscle adaptation to nutrition, exercise, aging, and chronic disease. This will be accomplished by (1) introducing skeletal muscle’s structure and function, (2) summarizing its adaptive responses to nutrition and contractile activity, and (3) reviewing changes with aging and chronic disease.

I Introduction

Skeletal muscle is a target organ for a variety of chemicals. Adverse or toxic effects on skeletal muscles can range from minor muscle weakness or slight pain to complete paralysis. Next to the brain, skeletal muscles are major targets for the toxicity of organophosphate (OP) nerve agents. Morbidity and mortality associated with OP intoxication is due to the effects of these compounds on skeletal muscles in general and muscles of respiration in particular. Deaths from overdose of OPs are due in part to respiratory paralysis by depolarizing neuromuscular blockade. Understanding the skeletal muscle system in the context of OP poisoning is interesting, yet very complex because muscles containing different fiber types often respond differently even to the same OP compound. The distinct features of slow and fast muscles are the most fascinating aspects of skeletal muscles in this area of research.

Skeletal muscles are enriched with cholinergic as well as noncholinergic elements that are directly or indirectly modulated by OP nerve agents. Motor innervation plays an important role in the regulation of many properties of skeletal muscles, including neuromuscular activity. Changes in the activities of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) appear to greatly modulate neuromuscular activity and can modifies neuromuscular transmission. At the cholinergic synapse, AChE plays an important role in the removal of acetylcholine (ACh) from the synaptic cleft. Inhibition of this enzyme by compounds such as OP nerve agents profoundly modifies neuromuscular transmission as seen in twitch potentiation, fasciculation, muscular weakness, and muscle cell death by necrosis or apoptosis. Being rich in metabolism, skeletal muscles are very vulnerable to OP-induced oxidative/nitrosative stress due to excess free radical generation. In the past two decades, interest in skeletal muscles has been enormous because of their involvement in intermediate syndrome and tolerance development related to the toxicity of OPs. OP-induced effects on skeletal muscles can occur at one or multiple sites (the nerve fiber, the nerve terminal, the junctional cleft, the motor endplate, or the myofibrils). This chapter describes structural and functional aspects of skeletal muscles in the context of OP nerve agents' toxicity.

Skeletal muscle toxicity is caused by a variety of chemicals, most notably organophosphate (OP) nerve agents. Toxic effects on skeletal muscles range from muscle weakness and pain to complete paralysis. The immediate effect of OP nerve agents (i.e., muscle hyperactivity) occurs by virtue of acetylcholinesterase (AChE) inactivation, leading to acetylcholine (ACh) accumulation at the neuromuscular junction (NMJ), causing overstimulation of nicotinic ACh receptors. OP nerve agents exert toxic effects in skeletal muscles due to the involvement of not only cholinergic, but also noncholinergic systems. Muscle excitotoxicity is associated with a complex cascade of events, such as excess free radical generation, lipid peroxidation, depletion of high-energy phosphates, high cytosolic Ca2+ levels, mitochondrial damage, and finally necrosis, apoptosis, and myopathy. In most circumstances, myopathy is untreatable, so prevention appears to be a better option. This chapter describes OP nerve agent-induced alterations in structural and functional properties of the muscle, cytotoxicity biomarkers, muscle involvement in tolerance development and in intermediate syndrome, and various strategies in the prevention and treatment of myopathy.

Abstract

Skeletal muscle is required for body locomotion. Multinucleated myofibers are the muscle cells that contract and generate the required force for skeletal muscle function. Sarcomeres are the basic unit of contraction in the myofiber and are composed of actin and myosin filaments. Multiple accessory proteins of these filaments are required for the maintenance of the structure and function of the sarcomere. Sarcomeres are connected to the plasma membrane and extracellular matrix to allow force transduction to the muscle. Sarcomere contraction is driven by the movement of myosin heads attached to actin in a cycle dependent of ATP hydrolysis and calcium. Sarcomeres form bundles of myofibrils that are surrounded by sarcoplasmic reticulum (SR) whose major function is to store calcium. Contraction is triggered by the release of calcium from the SR after depolarization of the T-tubules at the triads. Multiple genetic muscle disorders are caused by mutations in the components of the myofibers involved in muscle contraction.

4.4 Regeneration

Skeletal muscle has considerable regenerative capability, with satellite cells having a substantial role in this process. The stem cell environment or niche in adult skeletal muscle, bone marrow, and other tissues, described in detail elsewhere, can also differentiate and support homeostasis and regeneration. Regeneration is often apparent near and/or within areas of active necrosis and mononuclear phagocyte infiltration (Figure 17.6). Nuclei from viable regions of the myocyte and from responding satellite cells proliferate and become centrally located. The nuclei are enlarged and vesiculated with prominent nucleoli and are observed in long chains around day 3 after the injury. The sarcoplasm becomes basophilic and extends as ribbon-like projections along the remaining intact scaffolding of surrounding cells. These regenerating segments eventually bridge the gaps left by dissolution of sarcoplasm within the original fibers.

The effectiveness of regenerative attempts is limited by the severity of the original injury. Complete repair has been reported to occur approximately 3 weeks after injury. With extensive or persistent injury, fibrous connective tissue proliferation may outpace or impair muscle regeneration, resulting in scar formation rather than restoration of normal architecture and function. Severely necrotic or atrophic muscles may eventually also undergo partial replacement by adipose tissue.

Skeletal muscle regeneration is an area of increasing research focus. Indeed, the role of the immune system in muscle regeneration has been described with specialized macrophages (M2 phenotype) having roles in promoting repair and supporting satellite cell activity.

Introduction

Skeletal muscle, voluntary muscle, ordinary striated (as opposed to cardiac) muscle: these terms are not exactly synonymous, but collectively convey many of the familiar functional aspects of the muscles considered here. Together, they make up about 40% of the body's mass, and as with all muscles they are specialized for the generation of force. They range in size from the minute stapedius of the middle ear to the great quadriceps femoris of the anterior thigh. Trunk and limb muscles are perhaps the most familiar, but they also include such muscles as those of facial expression and the intrinsic muscles of the tongue. The forces that they generate are typically used to bring about the relative movements of their attachments, whether broad or narrow, such as in the opening and closing of joints between elements of the skeleton, or alterations in facial expression as in movements of the modiolus at the corner of the mouth with respect to the skull and mandible. The term ‘skeletal’ is therefore justified inasmuch as most of these muscles are more or less directly attached to skeletal elements, at least at one of their attachments. That most are also involved in consciously willed actions justifies their description as ‘voluntary,’ though it should be noted that it is a particular action rather than the direct activation of particular muscles that is typically under voluntary control. To give a specific example, our hands may be used to grasp, hold, point, applaud, or communicate linguistically in writing or signing (by no means an exhaustive list, of course), and it is immediately apparent that it is the action that is willed and not the precise activation of whichever of almost 40 muscles that operate the movements of each hand (some 20 intrinsic and 18 extrinsic heads are separately identifiable) (Wilson, 1999).

The characteristic, force-generating component of skeletal muscle is the muscle fiber, which will be the particular focus of this article. The fibers make up as much as 85% of the mass of a skeletal muscle, the remainder of which is composed of other essential components: nerve and blood supplies, lymphatic drainage, and connective tissues, including tendons and aponeuroses by which forces are transmitted between muscles and adjacent structures. The nature and significance of the alternating dark and light transverse bands, seen along the length of both skeletal and cardiac muscle fibers by early microscopists and much discussed by them, would eventually prove fundamental to understanding the process of force generation. Meanwhile, their very prominence gave rise to the common descriptive term ‘striated muscle.’ Skeletal muscle fibers are, however, unique among muscles in at least two important respects: (1) they are multinucleate cells, formed during development by the end-to-end fusion of mononuclear myoblasts (Stockdale and Holtzer, 1961) and (2) they are directly innervated by motoneurons whose cell bodies and dendrites are located in the central nervous system, either brain stem or spinal cord (Kernell, 2006).

VI CONTRACTILE PROPERTIES

Avian skeletal muscle contains actin and myosin filaments, arranged in the classical interdigitated pattern (see above). It is also known to contain the regulatory contractile proteins troponin, tropomyosin, and α-actinin (Allen et al., 1979; Devlin and Emerson, 1978, 1979). It is therefore assumed that the process of excitation–contraction coupling in avian muscle is essentially the same as that in mammalian muscle. Thus, certainly in focally innervated avian muscle fibers, it is assumed that muscle action potentials spread down the T-tubules to activate the contraction mechanism.

The contraction times of multiply innervated muscles with a Felderstruktur are 5 to 10 times slower than those of singly innervated muscles with a Fibrillenstruktur. This can be observed both in vivo (Hnik et al., 1967) and in vitro (Ginsborg, 1960b; Gordon and Vrbová, 1975; Gordon et al., 1977b). The time to reach one-half maximum response to a 40-Hz tetanus was about 400–500 msec in the chicken ALD, but only about 50 msec in the chicken PLD. Two other multiply innervated muscles of the chicken, the adductor profundus and the plantaris, have been shown to contract with velocities similar to that of the ALD (Barnard et al., 1982).

Contractile property development has been studied by Gordon et al. (1977a,b) in chicken ALD and PLD muscles. After 14–16 days incubation the contraction speeds of both embryo muscles were similar (time to half-maximal tension response to 40 Hz stimulation was ∼400–500 msec). Little change in the contraction speed of ALD muscles was observed during subsequent development. In contrast there was a progressive increase in the speed of contraction of PLD muscles

Calcium Cycling and the Control of Muscle Contraction: the EC Coupling Question

Normal contractile function in adult skeletal muscle requires large movements of calcium between cytoplasm and sarcoplasmic reticulum (SR). Exchanges with the extracellular spaces are considerably limited due to a variety of factors, namely the internal SR is a very efficient calcium sink; calcium entry through the plasmalemma’s calcium channels is small; sodium/calcium exchange and calcium pumping at the plasmalemma are of small magnitude; and depletion of the SR rarely occurs, so that store operated calcium entry plays a restricted role. However, overall calcium homeostasis is affected by exchanges at the plasmalemma and even small imbalances have a deleterious effect (see Chapter 56).

Historical key findings led to the classical textbook list of the sequential steps involved in the activation of muscle fibers: depolarization of the plasmalemma; inward spread of the depolarization along the transverse (T) tubular system; release of calcium for the SR; binding of calcium to troponin C; release of the TN-TM block to cross-bridge action. The local stimulation experiments (1) initially identified transversely oriented elements that mediated the effect of a local depolarization. Correlation of the inward spread of activation sites with the positioning of specific elements of the membrane system, the triads (2), the identification of the central elements of the triad as direct invaginations of the plasmalemma (3) (Figure 53.1A), and evidence for their continuity all across the fiber – hence the name transverse, T, tubules (Figure 53.1B) – firmly established the first step in excitation–contraction (EC) coupling.

Working from the other end, calcium was shown to be the intracellular transmitter that removes the troponin–tropomyosin inhibition of actomyosin interaction (4), and the muscle homogenate containing SR-derived vesicles was shown to be capable of actively taking up calcium ions through an ATP-dependent calcium pump (5). The ability of SR to lower Ca concentration to very low levels (6) made this organelle the necessary and sufficient agent in promoting relaxation.

Thus two major EC coupling concepts – Ca cycling by the SR and the link provided by T-tubules – were in the literature in the very early 1960s. This focused attention on the connection between T-tubules and SR at the triads, but the specific transmission step that allowed transduction of T-tubule depolarization into SR Ca release turned out to be very hard to elucidate and was not fully unraveled until recent times.

16.1 Introduction

This chapter covers the development and growth of avian skeletal muscle, beginning with a discussion of the structural diversity of skeletal muscle in different bird species. The chapter then proceeds to overview the embryonic origins of muscle, posthatch development, and growth, with a focus placed on the satellite cells. Satellite cells are adult myoblast stem cells that are responsible for all posthatch muscle growth. The next portion of the chapter deals with muscle fiber types, the mechanism of skeletal muscle contraction, and role of myogenic transcriptional regulatory factors. New emerging areas in avian skeletal muscle biology are also discussed, including satellite cell heterogeneity, extracellular matrix regulation of muscle growth and development, maternal inheritance of muscle morphological structure in turkeys, and the identification of novel genes involved in avian myogenesis.

Myokines and Exercise Factors: A Definition

The humoral nature of exercise factors released by working skeletal muscle was postulated more than 50 years ago (Goldstein, 1961), but the seminal work by Pedersen et al. (2003, 2004), and Pedersen and Febbraio (2012) set the stage for the myokine concept and provided convincing evidence for the existence of an exercise factor, in this case IL-6, which can be considered as the prototype myokine. As outlined in Box 3.1, we define a myokine as a peptide or protein secreted by skeletal muscle cells. This does not imply that these molecules are released to the circulation; instead, many of them (maybe even the majority) remain within skeletal muscle and exert auto- or paracrine functions. Contractile activity of myocytes involves activation of Ca++ and other signaling pathways that may regulate transcription and/or secretion of myokines. However, not all myokines are regulated by contractile activity, and we recommend that the release from myocytes is a mandatory criterion for the term “myokine”. Unfortunately, the situation is much more complex in that most likely none of the myokines is produced exclusively by myocytes. The best example is the prototype myokine IL-6 itself, which is also a well-known proinflammatory adipokine (see Chapter 2). We propose that the complete set of all peptides and proteins (organokinome) produced by all tissues comprises a limited number of molecules that gain specificity by (1) either a specific signature in the form of covalent modifications in a tissue-specific context, or (2) receptor-mediated processes at the level of target cells. This exciting topic is still unexplored and needs to be addressed in the future. We have used the term “adipomyokines” to emphasize this overlap between adipokines and myokines (Raschke and Eckel, 2013) (for detailed discussion, see Chapter 4).

In contrast to a myokine, an exercise factor is released to the circulation and is not necessarily a protein. Owing to modern metabolomics approaches, a number of metabolites have been identified as potential exercise factors. Compared with the myokine concept, the role of metabolites in mediating muscle-to-organ crosstalk appears much less important. This may be explained by a much higher information capacity of a protein being carried to a specific receptor and signaling pathway at a target cell.