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166 L.E. Gosselin same recruitment history due to its innate membrane fragility (Menke and Jockusch 1991; Petrof et al. 1993). Therefore, the same factors released fleetingly by normal muscle to promote wound healing are present chronically in dystrophic muscle and may have pathologic consequences. The presence of inflammatory cells is increased in skeletal muscle from patients with DMD and in mdx mice. The major infiltrating cell types in dystrophin- deficient muscle are macrophages (Engel and Arahata 1986; Spencer et al. 1997), T cells (Engel and Arahata 1986; Spencer et al. 1997), and eosinophils (Cai et al. 2000). Nguyen and Tidball (Nguyen and Tidball 2003) demonstrated that macrophages caused significant myotube lysis when co-cultured together. Furthermore, Wehling et al. (2001) reported that macrophage depletion from mdx muscles significantly reduced the concentration of regenerative muscle fibers. These findings support the hypothesis that macrophage accumulation secondary to inflammation can promote muscle injury. Given the persistent inflammatory response in dystrophic muscle, it is possible that an altered extracellular environment exists that promotes muscle fibrosis. Both TNF and TGF-b1 are produced by macrophages and are known to stimulate collagen metabolism. Moreover, their levels have been reported to be increased in muscular dystrophy (Bernasconi et al. 1995; Iannaccone et al. 1995; Lundberg et al. 1995; Tews and Goebel 1996; Murakami et al. 1999; Porreca et al. 1999; Hartel et al. 2001; Andreetta et al. 2006; Zhou et al. 2006). Given that the extracellular environment contains increased levels of and these cytokines, and because of their biologic actions observed in vitro, these cytokines may have prominent yet unknown in vivo roles in the pathogenesis of fibrosis in DMD. 6 Summary Regulation of collagen metabolism in normal and damaged skeletal muscle is com- plex and likely involves the interaction of several cell types and growth factors. Moreover, within a given organism, muscles with different activation patterns exhibit marked differences in collagen mRNA levels as well as collagen character- istics – indicative that mechanical load mediates collagen biosynthesis. Injured skeletal muscle contains elevated levels of inflammatory cells, which are known to secrete pro- and anti-inflammatory cytokines such as TNF-a and TGF-b1. Moreover, the expression of bFGF is also up-regulated in damaged and/or dystro- phic skeletal muscle. Significant evidence exists to suggest chronic inflammation plays a key role in the development of fibrosis in dystrophic muscle, though the mechanisms that regulate this process are not well understood. Both neutrophils and macrophages play important roles in the regulation of collagen remodeling post-injury by releasing various cytokines that mediate the behavior of inflamma- tory cells, fibroblasts and satellite cells. Moreover, the behavior of these cells can be affected by extrinsic factors such as basal levels of growth hormone, which changes with age. 167Skeletal Muscle Collagen: Age, Injury and Disease References Anderson, J. E., Bressler, B. H., Ovalle, W. K. (1988). Functional regeneration in the hindlimb skeletal muscle of the mdx mouse. Journal of Muscle Research and Cell Motility, 9, 499–515. Andreetta, F., Bernasconi, P., Baggi, F., Ferro, P., Oliva, L., Arnoldi, E., Cornelio, F., Mantegazza, R., Confalonieri, P. (2006). 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Lynch (ed.), Sarcopenia – Age-Related Muscle Wasting and Weakness, DOI 10.1007/978-90-481-9713-2_9, © Springer Science+Business Media B.V. 2011 Abstract Apoptosis is a well-conserve cellular disassembly process, which has been implicated in a variety of diseases. Unlike cells with a single nucleus, apop- totic signaling can target individual nuclei in multi-nucleated skeletal muscle cells without necessarily eliminating the entire cell (muscle fiber). This targeted apop- tosis or “nuclear apoptosis” appears to have a role in regulating aging-induced muscle loss (sarcopenia) by reducing the myofiber volume (i.e. cytoplasm) that can be supported in a single muscle fibre. Recent investigations indicate that apop- totic signaling in aged skeletal muscles occurs through three apoptotic pathways. The intrinsic or mitochondria apoptotic pathway has been most widely studied in muscle. Mitochondria dysfunction and increased mitochondria permeability lead to activation of cysteine-aspartic acid proteases (caspases) and eventually DNA fragmentation in sarcopenia. The death receptor (extrinsic) apoptotic pathway has been strongly implicated in sarcopenia and other conditions of muscle loss with aging or disuse. TNF-a is thought to initiate apoptotic signaling via the death receptor, and this can proceed to activate the effort proteases (e.g., caspase 3) independent from mitochondria signaling. Nevertheless, there is some cross-talk between the intrinsic and the extrinsic apoptotic pathways. Finally, a few studies have shown data to suggest that the endoplasmic reticulum-stress apoptotic path- way may also have a role in sarcopenia, although the importance of this pathway relative to the other two pathways is less clear. Both myonuclei and satellite cells appear to be susceptible to nuclear apoptosis in sarcopenia. S.E. Alway (*) Department of Exercise Physiology, and Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Robert C Byrd Health Sciences Center, 1 Medical Center Drive, Morgantown, WV 26506, USA e-mail: salway@hsc.wvu.edu P.M. Siu Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China e-mail: htpsiu@inet.polyu.edu.hk Nuclear Apoptosis and Sarcopenia Stephen E. Alway and Parco M. Siu 174 S.E. Alway and P.M. Siu Keywords Nuclear cell death • Apoptosis • Skeletal myofiber • Satellite cell • Mitochondria • Muscle atrophy 1 Apoptosis Apoptosis is a fundamental biological process that is highly conserved among species ranging from worm to human (Ellis et al. 1991; Yuan 1996) for elimination of cells from tissues in an energy dependent manner. The term “apoptosis” origi- nates from Greek (apo – from; ptosis – falling) which means “falling off”. The phenomenon of apoptosis was first systematically described in nematode Caenorhabditis elegans by Kerr and colleagues (Kerr et al. 1972). The distinctive morphological characteristics of apoptosis include cell shrinkage, cell membrane blebbing, chromatin condensation, internucleosomal degradation of chromosomal DNA, and formation of membrane-bound fragments called apoptotic bodies (Kerr et al. 1972). The morphological and biochemical characteristics of apoptosis are unique and clearly distinguish it from necrotic cell death. Homologous apoptotic regulatory death genes have been identified in a variety of organisms including mammals and humans (Sulston and Horvitz 1977). In the past several decades, there has been a better understanding of the biologi- cal role and the regulatory mechanisms of apoptosis in life science and disease and aging. Apoptosis is necessary for the elimination of damaged, aberrant, or harmful cells. Apoptosis also participates in normal embryonic development, tissue turnover, and immunological function (Thompson 1995). Apoptosis coordinates the balance among cell proliferation, differentiation, and cell death in multicellular organisms. Therefore, it is reasonable to conclude that health would be threatened if apoptosis is not adequately maintained or if it is disrupted. In fact, aberrant regu- lation of apoptosis has been demonstrated to contribute to the pathogenesis of severe diseases including viral infections, cancers, autoimmune diseases (e.g., systemic lupus erythematosus and rheumatoid arthritis), loss of pancreatic beta-cell in diabetes mellitus, toxin-induced liver disease, and acquired immune deficiency syndrome (AIDS), myocardial and cerebral ischemic injuries and neurodegenera- tive diseases and muscle loss associated with aging such as Alzheimer’s and Parkinson’s diseases (Williams 1991; Thompson 1995; Duke et al. 1996; Yuan and Yankner 2000; Lee and Pervaiz 2007; McMullen et al. 2009; Cacciapaglia et al. 2009; Campisi and Sedivy 2009). 2 Muscle Specific Apoptotic Signalling – Nuclear Apoptosis Apoptosis was initially described as a process that was responsible for elimination of entire cells, and this was essential for maintaining the homeostasis of cell growth and death especially in cells with a high proliferative rate. In the context of single cells, the term apoptosis has a clearly defined process leading to elimination of the nucleus and therefore the cell. However, the better term to describe this same process in 175Nuclear Apoptosis and Sarcopenia multinucleated post mitotic cell populations including cardiomyocytes and skeletal myofibres is “nuclear apoptosis”. This is because elimination of a single nucleus can occur without the death of the entire (multinucleated) muscle cell although this may result in smaller cells. We propose that the process of apoptotic loss of myonuclei in skeletal muscle should be best described as “nuclear apoptosis”. Nuclear apoptosis can occur without inflammation or disturbing adjacent proteins or organelles. The concept of “nuclear apoptosis” (i.e., death of a nucleus without death of the entire cell) is intriguing and exciting. By definition, nuclear apoptosis involves cell signalling that is so precise that specific individual nuclei can be targeted for elimi- nation in a multinucleated skeletal myofiber without targeting other nuclei. Thus, nuclear apoptosis requires amazingly precise targeting of some nuclei but not others within a single muscle fibre. Evidence accumulated over the last several years has shown that apoptosis is a significant contributor to muscle degeneration (Primeau et al. 2002; Adhihetty and Hood 2003; Dirks and Leeuwenburgh 2005; Tews 2005; Siu and Alway 2005a, 2006b; Siu et al. 2006; Pistilli et al. 2006b; Adhihetty et al. 2008, 2009; Marzetti et al. 2008c, 2009b; Lees et al. 2009; Smith et al. 2009). However, apoptosis in skeletal muscle is unique for several reasons. First, skeletal muscle is multi-nucle- ated. Thus, the removal of one myonucleus by apoptosis will not produce “whole- sale” muscle cell death, but it does result in a loss of gene expression within the local myonuclear domain, potentially leading to cellular atrophy. Second, muscle contains two morphologically and biochemically distinct subfractions of mitochon- dria (subsarcolemmal, SS and intermyofibrillar, IMF) that exist in different regions of the fibre could produce regional differences in the sensitivity to apoptotic stimuli within the cell (Adhihetty et al. 2007a, 2008, 2009). Third, skeletal muscle is a malleable tissue capable of changing its mitochondrial content and/or composition in response to chronic alterations in muscle use or disuse. Such variations in mito- chondrial content and/or composition can undoubtedly influence the degree of organelle-directed apoptotic signalling in skeletal muscle. Evidence that not all myonuclei in a single myofiber become apoptotic during muscle loss has been observed in experimental denervation and denervation-asso- ciated disease (e.g., infantile spinal muscular atrophy). This further supports the hypothesis of “nuclear apoptosis” in modulating the myofiber volume by control- ling the successive myofiber segments. The hypothesis of nuclear apoptosis is consistent with the proposed “nuclear domain hypothesis” which explains the phe- nomenon of cell size remodelling of myofiber by adding or subtracting nuclei because each nucleus controls a specifically defined cytoplasmic area (Fig. 1). The skeletal myofiber is a differentiated but highly plastic cell type which adapts to loading and unloading. The nuclear domain hypothesis predicts that a nucleus con- trols a defined volume of cellular territory in each myofiber. Therefore, addition of extra nuclei (from satellite cells) into the myofiber is required to support the incre- ment of cell size in order to achieve muscle hypertrophy and removal of the myo- nuclei is needed to allow the muscle to atrophy. If fewer nuclei are available, less cytoplasmic area could be supported. Generally, there is a tight relationship between nuclear number and muscle fibre cross-sectional area and volume. Nevertheless, this relationship is not perfect, because the nuclear domain increases . Age and training alter collagen characteristics in fast- and slow-twitch rat limb muscle. Journal of Applied Physiology, 75, 1670–1674. 173 G.S. Lynch (ed.), Sarcopenia – Age-Related Muscle Wasting. and humans (Sulston and Horvitz 1977). In the past several decades, there has been a better understanding of the biologi- cal role and the regulatory mechanisms of apoptosis in life science and. (1988). Age-related changes in the proportion of types I and III collagen. Mechanisms of Ageing and Development, 45, 203–212. McAnulty, R. & Laurent, G. J. (1987). Collagen synthesis and degradation