Altered cross-bridge properties in skeletal muscle dystrophies

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.

Keywords: cross-bridge kinetics; muscle dystrophy; myopathies; myosin; skeletal muscle.

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.

Figure 2

The CB cycle. Step a: attachment of myosin to actin. This step begins with the “weak binding” of actin (in magenta) to the myosin head (in brown). A stereospecific interaction between actin and myosin leads to strong binding of actin to myosin. Step b: power stroke. The loss of inorganic phosphate (Pi) is assumed to trigger the onset of the power stroke and a reversal of the previous conformational bent. Step c: ADP release step. The power stroke induces reopening of the nucleotide binding pocket and ADP release. Step d: ATP binding. ATP can then rapidly bind to myosin which dissociates from actin. Step e: ATP hydrolysis. ATP is then rapidly hydrolyzed to ADP and Pi.

Figure 3

Transmission of the forces generated in sarcomere. The dystrophin-glycoprotein complex is preferentially located at the costamere, a protein network that reside at the sarcolemma membrane in register with the Z-lines of sarcomeres and that is critical in the lateral transmission of forces generated by the CB to the ECM and neighboring muscle fibers. Dystrophin deficiency at the lateral membrane alters costamere assembly and thus may impair the efficacy of lateral force transmission.