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Altered cross-bridge properties in skeletal muscle dystrophies.

Guellich A, Negroni E, Decostre V, Demoule A, Coirault C - Front Physiol (2014)

Bottom Line: This mechanical process is regulated by intracellular Ca(2+) through the thin filament-associated regulatory proteins i.e.; troponins and tropomyosin.Micro-architectural change in myofilament is another mechanism of altered cross-bridge performance.In this review, we provide an overview about changes in cross-bridge performance in skeletal MDs and discuss their ultimate impacts on striated muscle function.

View Article: PubMed Central - PubMed

Affiliation: Service de Cardiologie, Hôpital Henri Mondor, University Paris-Est Créteil Créteil, France ; Equipe 8, Institut National de la Santé et de la Recherche Médicale Créteil, France.

ABSTRACT
Force and motion generated by skeletal muscle ultimately depends on the cyclical interaction of actin with myosin. This mechanical process is regulated by intracellular Ca(2+) through the thin filament-associated regulatory proteins i.e.; troponins and tropomyosin. Muscular dystrophies are a group of heterogeneous genetic affections characterized by progressive degeneration and weakness of the skeletal muscle as a consequence of loss of muscle tissue which directly reduces the number of potential myosin cross-bridges involved in force production. Mutations in genes responsible for skeletal muscle dystrophies (MDs) have been shown to modify the function of contractile proteins and cross-bridge interactions. Altered gene expression or RNA splicing or post-translational modifications of contractile proteins such as those related to oxidative stress, may affect cross-bridge function by modifying key proteins of the excitation-contraction coupling. Micro-architectural change in myofilament is another mechanism of altered cross-bridge performance. In this review, we provide an overview about changes in cross-bridge performance in skeletal MDs and discuss their ultimate impacts on striated muscle function.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the main mechanisms leading to muscle weakness in MDs. Altered CB cycle in muscular dystrophy can arise from multiples causes including progressive loss of muscle tissue due to necrosis, fibrosis, atrophy, or oxidative damage, micro-architectural alterations in myofilaments, altered redox regulation or pathological changes in contractile protein isoforms. These abnormalities in turn directly reduce the number, the force, the kinetics of active CBs or the transmission of force produced by the CBs.
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Figure 1: Schematic representation of the main mechanisms leading to muscle weakness in MDs. Altered CB cycle in muscular dystrophy can arise from multiples causes including progressive loss of muscle tissue due to necrosis, fibrosis, atrophy, or oxidative damage, micro-architectural alterations in myofilaments, altered redox regulation or pathological changes in contractile protein isoforms. These abnormalities in turn directly reduce the number, the force, the kinetics of active CBs or the transmission of force produced by the CBs.

Mentions: Muscular dystrophies (MDs) are a group of more than 30 clinical and molecular heterogeneous genetic disorders that cause progressive degeneration of the skeletal muscle fibers. They are characterized by severe muscle weakness that generally affects limb, axial, and/or facial muscles to a variable extent. The age of onset, severity and rate of progression greatly vary in the different forms of MD. The primary cause of various forms of MDs is an individual mutation in genes encoding a wide variety of proteins, including extracellular matrix (ECM) proteins, transmembrane, and membrane-associated proteins, cytoplasmic proteases and nuclear proteins. Detailed classification and list of causative genes in MD have been recently reviewed (Cohn and Campbell, 2000; Flanigan, 2012; Kaplan and Hamroun, 2012; Mercuri and Muntoni, 2013). Although still incompletely understood, considerable progress has been now made to reveal the pathophysiological mechanisms in MDs. It has been shown that most MDs share common pathologic features, such as altered Ca2+ homeostasis, infiltration of muscle tissue by inflammatory immune cells, accretion of proinflammatory and profibrotic cytokines, activation of proteolytic enzymes, metabolic/mitochondrial alterations, intracellular accumulation of reactive oxygen species (ROS) production, and/or defective autophagy, which can contribute to muscle wasting. At the earliest stages of the disease, reduced myofibrillar protein content can occur in apparent uninjured fibers, secondary to an imbalance between protein synthesis and proteolysis (McKeran et al., 1977; Warnes et al., 1981). Then, successive rounds of degeneration and regeneration lead to fibrosis and fatty replacement of muscle tissue and in turn reduce the number of potential cross-bridges (CBs) generating force (Figure 1). In addition, functional changes in the CB properties may contribute to muscle weakness in distinct types of muscle disease. It is well-established that shift in the relative myosin isoform expression is associated with modifications of the kinetics of actomyosin interactions (Bar and Pette, 1988; Schiaffino et al., 1989; Schiaffino and Reggiani, 1996). However, there are also increasing evidences that CB properties can change with no change in myosin isoform content (Coirault et al., 2002; Canepari et al., 2009), suggesting that post-translational modifications of contractile proteins have significant role in muscle weakness (Figure 1). The present review focuses on the changes in the function of contractile proteins and in CB performance that may occur in the context of skeletal muscle dystrophies (MDs) and their contribution to the pathophysiological mechanisms of these diseases.


Altered cross-bridge properties in skeletal muscle dystrophies.

Guellich A, Negroni E, Decostre V, Demoule A, Coirault C - Front Physiol (2014)

Schematic representation of the main mechanisms leading to muscle weakness in MDs. Altered CB cycle in muscular dystrophy can arise from multiples causes including progressive loss of muscle tissue due to necrosis, fibrosis, atrophy, or oxidative damage, micro-architectural alterations in myofilaments, altered redox regulation or pathological changes in contractile protein isoforms. These abnormalities in turn directly reduce the number, the force, the kinetics of active CBs or the transmission of force produced by the CBs.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196474&req=5

Figure 1: Schematic representation of the main mechanisms leading to muscle weakness in MDs. Altered CB cycle in muscular dystrophy can arise from multiples causes including progressive loss of muscle tissue due to necrosis, fibrosis, atrophy, or oxidative damage, micro-architectural alterations in myofilaments, altered redox regulation or pathological changes in contractile protein isoforms. These abnormalities in turn directly reduce the number, the force, the kinetics of active CBs or the transmission of force produced by the CBs.
Mentions: Muscular dystrophies (MDs) are a group of more than 30 clinical and molecular heterogeneous genetic disorders that cause progressive degeneration of the skeletal muscle fibers. They are characterized by severe muscle weakness that generally affects limb, axial, and/or facial muscles to a variable extent. The age of onset, severity and rate of progression greatly vary in the different forms of MD. The primary cause of various forms of MDs is an individual mutation in genes encoding a wide variety of proteins, including extracellular matrix (ECM) proteins, transmembrane, and membrane-associated proteins, cytoplasmic proteases and nuclear proteins. Detailed classification and list of causative genes in MD have been recently reviewed (Cohn and Campbell, 2000; Flanigan, 2012; Kaplan and Hamroun, 2012; Mercuri and Muntoni, 2013). Although still incompletely understood, considerable progress has been now made to reveal the pathophysiological mechanisms in MDs. It has been shown that most MDs share common pathologic features, such as altered Ca2+ homeostasis, infiltration of muscle tissue by inflammatory immune cells, accretion of proinflammatory and profibrotic cytokines, activation of proteolytic enzymes, metabolic/mitochondrial alterations, intracellular accumulation of reactive oxygen species (ROS) production, and/or defective autophagy, which can contribute to muscle wasting. At the earliest stages of the disease, reduced myofibrillar protein content can occur in apparent uninjured fibers, secondary to an imbalance between protein synthesis and proteolysis (McKeran et al., 1977; Warnes et al., 1981). Then, successive rounds of degeneration and regeneration lead to fibrosis and fatty replacement of muscle tissue and in turn reduce the number of potential cross-bridges (CBs) generating force (Figure 1). In addition, functional changes in the CB properties may contribute to muscle weakness in distinct types of muscle disease. It is well-established that shift in the relative myosin isoform expression is associated with modifications of the kinetics of actomyosin interactions (Bar and Pette, 1988; Schiaffino et al., 1989; Schiaffino and Reggiani, 1996). However, there are also increasing evidences that CB properties can change with no change in myosin isoform content (Coirault et al., 2002; Canepari et al., 2009), suggesting that post-translational modifications of contractile proteins have significant role in muscle weakness (Figure 1). The present review focuses on the changes in the function of contractile proteins and in CB performance that may occur in the context of skeletal muscle dystrophies (MDs) and their contribution to the pathophysiological mechanisms of these diseases.

Bottom Line: This mechanical process is regulated by intracellular Ca(2+) through the thin filament-associated regulatory proteins i.e.; troponins and tropomyosin.Micro-architectural change in myofilament is another mechanism of altered cross-bridge performance.In this review, we provide an overview about changes in cross-bridge performance in skeletal MDs and discuss their ultimate impacts on striated muscle function.

View Article: PubMed Central - PubMed

Affiliation: Service de Cardiologie, Hôpital Henri Mondor, University Paris-Est Créteil Créteil, France ; Equipe 8, Institut National de la Santé et de la Recherche Médicale Créteil, France.

ABSTRACT
Force and motion generated by skeletal muscle ultimately depends on the cyclical interaction of actin with myosin. This mechanical process is regulated by intracellular Ca(2+) through the thin filament-associated regulatory proteins i.e.; troponins and tropomyosin. Muscular dystrophies are a group of heterogeneous genetic affections characterized by progressive degeneration and weakness of the skeletal muscle as a consequence of loss of muscle tissue which directly reduces the number of potential myosin cross-bridges involved in force production. Mutations in genes responsible for skeletal muscle dystrophies (MDs) have been shown to modify the function of contractile proteins and cross-bridge interactions. Altered gene expression or RNA splicing or post-translational modifications of contractile proteins such as those related to oxidative stress, may affect cross-bridge function by modifying key proteins of the excitation-contraction coupling. Micro-architectural change in myofilament is another mechanism of altered cross-bridge performance. In this review, we provide an overview about changes in cross-bridge performance in skeletal MDs and discuss their ultimate impacts on striated muscle function.

No MeSH data available.


Related in: MedlinePlus