Random myosin loss along thick-filaments increases myosin attachment time and the proportion of bound myosin heads to mitigate force decline in skeletal muscle.
Diminished skeletal muscle performance with aging, disuse, and disease may be partially attributed to the loss of myofilament proteins. Several laboratories have found a disproportionate loss of myosin protein content relative to other myofilament proteins, but due to methodological limitations, the structural manifestation of this protein loss is unknown. To investigate how variations in myosin content affect ensemble cross-bridge behavior and force production we simulated muscle contraction in the half-sarcomere as myosin was removed either (i) uniformly, from the Z-line end of thick-filaments, or (ii) randomly, along the length of thick-filaments. Uniform myosin removal decreased force production, showing a slightly steeper force-to-myosin content relationship than the 1:1 relationship that would be expected from the loss of cross-bridges. Random myosin removal also decreased force production, but this decrease was less than observed with uniform myosin loss, largely due to increased myosin attachment time (ton) and fractional cross-bridge binding with random myosin loss. These findings support our prior observations that prolonged ton may augment force production in single fibers with randomly reduced myosin content from chronic heart failure patients. These simulations also illustrate that the pattern of myosin loss along thick-filaments influences ensemble cross-bridge behavior and maintenance of force throughout the sarcomere.
Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99164, United States. Electronic address: btanner@vetmed.wsu.edu.
Bertrand C W
BC
Tanner
Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99164, United States.
Mark
M
McNabb
Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, United States.
Bradley M
BM
Palmer
Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, United States; Department of Medicine, University of Vermont, Burlington, VT 05405, United States.
Michael J
MJ
Toth
Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, VT 05405, United States.
Mark S
MS
Miller
D001696:Biomechanical Phenomena; D003198:Computer Simulation; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism*; D009218:Myosins / Q000737:chemistry / Q000378:metabolism*; D012518:Sarcomeres / Q000737:chemistry / Q000378:metabolism*
D009218:Myosins
Computational modeling; Cross-bridge kinetics; Muscle mechanics; Sarcomere structure; Thick-filaments