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WIREs Syst Biol Med
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Systems analysis of biological networks in skeletal muscle function

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Abstract Skeletal muscle function depends on the efficient coordination among subcellular systems. These systems are composed of proteins encoded by a subset of genes, all of which are tightly regulated. In the cases where regulation is altered because of disease or injury, dysfunction occurs. To enable objective analysis of muscle gene expression profiles, we have defined nine biological networks whose coordination is critical to muscle function. We begin by describing the expression of proteins necessary for optimal neuromuscular junction function that results in the muscle cell action potential. That action potential is transmitted to proteins involved in excitation–contraction coupling enabling Ca2+ release. Ca2+ then activates contractile proteins supporting actin and myosin cross‐bridge cycling. Force generated by cross‐bridges is transmitted via cytoskeletal proteins through the sarcolemma and out to critical proteins that support the muscle extracellular matrix. Muscle contraction is fueled through many proteins that regulate energy metabolism. Inflammation is a common response to injury that can result in alteration of many pathways within muscle. Muscle also has multiple pathways that regulate size through atrophy or hypertrophy. Finally, the isoforms associated with fast muscle fibers and their corresponding isoforms in slow muscle fibers are delineated. These nine networks represent important biological systems that affect skeletal muscle function. Combining high‐throughput systems analysis with advanced networking software will allow researchers to use these networks to objectively study skeletal muscle systems. WIREs Syst Biol Med 2013, 5:55–71. doi: 10.1002/wsbm.1197 This article is categorized under: Models of Systems Properties and Processes > Mechanistic Models Physiology > Mammalian Physiology in Health and Disease Laboratory Methods and Technologies > RNA Methods

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Neuromuscular junction (NMJ). Motor neurons release the neurotransmitter acetylcholine, which triggers an action potential. NMJ formation is also induced by motor neuron factors that signal muscle proteins. For all figures, we use the following node conventions: (blue circle) entrez gene symbols, (blue circle within grayed box) complexes, (blue triangle) non‐protein molecules, (blue square with rounded edges) modules or functions. There are the following interactions: (plus in white circle) positive, (minus in red circle) negative, (black circle) binding, (double back slash) intermediate, and (question mark with circle) unknown. There are the following lines: (solid thick line) basic, (solid thick line with arrow) A proceeds to B, (horizontal thin line with vertical right end thick line) A does not proceed to B, and (curved arrow) translocation of A. Genes within complexes are listed in Table S1, Supporting Information. Some complexes are interacting proteins; however, others are multiple isoforms of a protein that have the same function.

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Muscle fiber type (FT). Genes that have similar function but are expressed specifically in either a fast or slow muscle FT are listed here. MYH is the major determinant of FT, but numerous genes exist that are coregulated in the various FTs.

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Muscle hypertrophy and atrophy. Multiple pathways determine muscle size. IGF1 signals fiber growth and increased protein production. MAPKs can elicit muscle myogenic factors in response to stresses. Autocrine factor MSTN limits muscle growth through the SMAD pathway.

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Inflammation. Early macrophages and neutrophils enter damaged muscle to clear debris and produce an inflammatory signal. If present chronically, inflammation can lead to secondary tissue degradation. Secondary macrophages enter to limit inflammatory signals and repair muscle.

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Energy metabolism. Muscles use ATP as their energy source for contraction and much of relaxation. ATP is generated both glycolytically and oxidatively in the muscle from glucose or fatty acids, respectively. Muscle has energy‐sensing mechanisms that permit adaptation of metabolic systems to changes in energy demand.

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Extracellular matrix (ECM). Provides the network for intracellular loads to be transmitted extracellularly. The basal lamina is a mesh‐like network, while the fibrillar ECM is made up of larger collagen fibrils and associated proteins. Several important growth factors are involved in ECM formation and several enzyme systems regulate its state.

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Cytoskeleton. Muscle force generated in the sarcomere is transmitted from myofibrils to the sarcolemma through the dystroglycan complex or integrins. Loads are transmitted to intracellular organelles through the intermediate filament network. The cytoskeleton also bears passive muscle loads and can limit the normal range of motion at different joints.

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Muscle contraction (MC). Myosin binds to actin and undergoes cross‐bridge cycling to produce contractile force. Myosin (thick) and actin (thin) filaments slide past each other during contraction. Sarcomeres are separated by Z‐discs. The force generated by the myosin cross‐bridge powers active MC.

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Excitation–contraction coupling. Action potentials travel into the T‐tubule system and induce Ca2+ release from the sarcoplasmic reticulum (SR) through the ryanodine receptor. Intracellular Ca2+ triggers muscle contraction and is then pumped back into the Sr. Ca2+ also plays a role in several critical intracellular signaling pathways that regulate muscle mass and muscle fiber type.

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Models of Systems Properties and Processes > Mechanistic Models
Laboratory Methods and Technologies > RNA Methods
Physiology > Mammalian Physiology in Health and Disease

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