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WIREs Syst Biol Med
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Systems biology of skeletal muscle: fiber type as an organizing principle

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Abstract Skeletal muscle force generation and contraction are fundamental to countless aspects of human life. The complexity of skeletal muscle physiology is simplified by fiber type classification where differences are observed from neuromuscular transmission to release of intracellular Ca2+ from the sarcoplasmic reticulum and the resulting recruitment and cycling of cross‐bridges. This review uses fiber type classification as an organizing and simplifying principle to explore the complex interactions between the major proteins involved in muscle force generation and contraction. WIREs Syst Biol Med 2012. doi: 10.1002/wsbm.1184 This article is categorized under: Physiology > Mammalian Physiology in Health and Disease Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models

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Four motor unit types—slow (type S), fast‐twitch fatigue resistant (type FR), fast‐twitch fatigue intermediate (type FInt), and fast‐twitch fatigable (type FF)—are classified based on the contractile and fatigue properties of the innervated muscle fibers. Each motor unit type comprises a specific fiber that expresses a single MyHC isoform. (Reprinted with permission from Ref 11. Copyright 1994 Elsevier Ltd.)

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(a) Model of the signaling pathways regulating myosin protein synthesis and degradation. Contributors to the regulation of protein synthesis are protein kinase B (Akt), p44/42 MAPK (ERK), and AMP‐activated protein kinase (AMPK), resulting in activation of their downstream targets, mammalian target of rapamycin (mTOR), glycogen synthase kinase‐3β (GSK3β), MAPK‐interacting kinases 1/2 (MNK1/2), p70S6 kinase (p70S6K), eIF4E‐binding protein 1 (4EBP1), and eukaryotic initiation factors 2B and 4E (eIF2B and eIF4E). Akt is also responsible for phosphorylation of forkhead box protein (FoxO) that is involved in protein degradation. After phosphorylation by Akt, FoxO exits the nucleus and becomes inactive, thus preventing protein degradation. When Akt activity is suppressed, FoxO is dephosphorylated, translocates to the nucleus, and induces protein degradation through the ubiquitin‐proteasome pathway. (b) Western blot analysis of total protein ubiquitination after varying time periods of unilateral phrenic nerve denervation (D) or sham (S) procedure. Overall ubiquitination increased and peaked after 5 days of denervation. (c) Total protein synthesis rates by tyrosine incorporation assay. Protein synthesis increased and remained elevated beginning at 3 days postdenervation. (Reprinted with permission from Ref 66. Copyright 2009 The American Physiological Society)

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(a) Confocal image of a single diaphragm muscle fiber clearly showing sarcomeres (membrane stained with RH414—red) and myonuclei (stained with propidium iodide—green). (b) Representative real‐time RT‐PCR amplification curves for various MyHC isoforms. (Reprinted with permission from Ref 61. Copyright 2006 The American Physiological Society). (c) Representative electrophoretic determination of MyHC isoform expression in single rat diaphragm muscle fibers. The concentration of MyHC extracted from single fibers was compared to known concentrations of MyHC. (Reprinted with permission from Ref 48. Copyright 2007 The American Physiological Society)

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(a) Experimentally, the rate of ATP consumption in single permeabilized muscle fibers can be measured based on NADH fluorescence extinction using a stop flow technique in which ATP hydrolysis is coupled with the reduction of NADH to NAD. (b) The force–velocity of shortening and force–power output relationships of a skeletal muscle fiber. ATP consumption rate (indicated by arrows) of a muscle fiber varies with force and velocity of shortening and peaks at maximal power output. (Reprinted with permission from Ref 41. Copyright 1997 European Respiratory Society)

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(a) Cross‐bridge cycle between bound and unbound states with apparent rate constants for cross‐bridge attachment (fapp) and detachment (gapp). Force depends on the number of available myosin heads per half‐sarcomere (n), the fraction of cross‐bridges in the strongly bound state (αfs), and the average force generated per cross‐bridge (F). The ATP consumption rate during cross‐bridge cycling occurs throughout the muscle fiber and thus also depends on the number of half‐sarcomeres in series (b). (Reprinted with permission from Ref 5. Copyright 2001 The American Physiological Society). (b) Cross‐bridge cycling rate can be estimated by the rate constant for force redevelopment after rapid release (all cross‐bridges broken) and restretch of a single permeabilized muscle fiber (ktr) and varies across fibers expressing different MyHC isoforms. (c) fapp can be estimated by the rate of force development resulting from rapid flash‐photolytic release of caged Ca2+ and activation of the muscle fiber. (d) gapp can be estimated by rapid removal of Ca2+ following flash‐photolytic release of a caged Ca2+ chelator and measuring the rate of force relaxation. Both fapp and gapp are faster in fibers expressing MyHC2X compared with those expressing MyHCslow.

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(a) A nerve action potential initiates a transient increase in myoplasmic Ca2+ concentration that precedes the force response of a muscle fiber. (b) The force–Ca2+ relationship is shifted leftward (increased Ca2+ sensitivity) in type I fibers (MyHCslow) compared with type IIa (MyHC2A), IIx (MyHC2X), and type IIb (MyHC2B) fibers. (Reprinted with permission from Ref 37. Copyright 1999 The American Physiological Society)

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(a) Representative confocal image of neuromuscular junction (NMJ) showing motor axons down to the presynaptic terminal (immunoreactivity for neurofilamin—red), motor end plates (cholinergic receptors fluorescently labeled using α‐bungarotoxin—green), and muscle fibers (labeled with an antibody specific to the MyHC2B isoform—blue). (b) Electron micrograph showing the presynaptic and postsynaptic elements of a NMJ. (Reprinted with permission from Ref 31. Copyright 2007 The American Physiological Society). (c) Electrophysiological recording of spontaneous miniature end‐plate potentials (mEPPs) and an evoked EPP response. The presynaptic terminal was visualized by uptake of a styryl dye FM4‐64. (d) Neuromuscular transmission failure induced by repetitive nerve stimulation is reflected by the difference in muscle force generated by nerve stimulation compared with that induced by periodic (every 15 seconds) direct muscle stimulation. (Reprinted with permission from Ref 32. Copyright 2004 John Wiley and Sons)

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Muscle force generation depends on muscle fiber length. Underlying the force–length relationship of muscle is the overlap of thick (red and black) and thin (yellow) filaments within a sarcomere that determines the number of cross‐bridges that can form during muscle activation.

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(a) Muscle fibers comprise myofibrils that contain repeating arrangements of sarcomeres, which give muscle its striated appearance as seen by transmission electron microscopy. The primary components of the sarcomere are thick and thin filaments, which interact by cross‐bridge formation and slide past each other during muscle contraction. (b) The crystalline organization of myosin (red) and actin (yellow) filaments creating a myofilament lattice is clearly seen in an electron micrograph of a muscle fiber cross section.

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