Browsing by Author "DuVall, Michael M."
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Item Open Access Altered mechanical properties of titin immunoglobulin domain 27 in the presence of calcium(European Biophysics Journal, 2013-04) DuVall, Michael M.; Gifford, Jessica L.; Amrein, Matthias W.; Herzog, WalterTitin (connectin) based passive force regulation has been an important physiological mechanism to adjust to varying muscle stretch conditions. Upon stretch, titin behaves as a spring capable of modulating its elastic response in accordance with changes in muscle biochemistry. One such mechanism has been the calcium-dependent stiffening of titin domains that renders the spring inherently more resistant to stretch. This transient titin-calcium interaction may serve a protective function in muscle, which could preclude costly unfolding of select domains when muscles elongate to great lengths. To test this idea, fluorescence spectroscopy was performed revealing a change in the microenvironment of the investigated immunoglobulin domain 27 (I27) of titin with calcium. Additionally, an atomic force microscope was used to evaluate the calcium-dependent regulation of passive force by stretching eight linked titin I27 domains until they unfolded. When stretching in the presence of calcium, the I27 homopolymer chain became stabilized, displaying three novel properties: (1) higher stretching forces were needed to unfold the domains, (2) the stiffness, measured as a persistence length (PL), increased and (3) the peak-to-peak distance between adjacent I27 domains increased. Furthermore, a peak order dependence became apparent for both force and PL, reflecting the importance of characterizing the dynamic unfolding history of a polymer with this approach. Together, this novel titin Ig-calcium interaction may serve to stabilize the I27 domain permitting titin to tune passive force within stretched muscle in a calcium-dependent manner.Item Open Access Molecular mechanisms of muscle force regulation: a role for titin?(Exercise Sport Science Reviews, 2012-01) Herzog, Walter; DuVall, Michael M.; Leonard, Timothy R.Muscle contraction and force regulation is thought to occur exclusively through the interaction of the contractile proteins actin and myosin and in accordance with the assumptions underlying the cross-bridge theory. Here, we demonstrate that a third protein, titin, plays a major role in muscle force regulation, particularly for eccentric contractions and at long muscle and sarcomere lengths.Item Open Access Muscular loading of joints triggers cellular secretion of PRG4 into the joint fluid(Journal of Biomechanics, 2013-04-26) Abusara, Ziad; Krawetz, Roman J.; Steele, Bridgett L.; DuVall, Michael M.; Schmidt, Tannin A.; Herzog, WalterWe developed a novel testing system that allows quantification of joint loading and permits analysis of changes in total protein and PRG4 contents in joint fluid of intact knees in live mice. A sequence of 15 repeat, isometric muscular contractions of "low" intensity (less than 50% of the maximal isometric muscular force), and "high" intensity (greater than 55% of maximal) were applied repeatedly (up to five times with a 15 min rest between contractions) to the mouse knee. Increases in knee joint loading were accompanied with significant increases in total protein (p<0.0001) and PRG4 concentrations in the synovial fluid. Total protein and PRG4 concentrations decreased with repeated "high" intensity loading. However, the addition of cell secretion inhibitors to the knee prior to muscular loading resulted in PRG4 levels that remained below the detection limit for all loading conditions. These results suggest that changes in synovial fluid proteins and PRG4 concentrations upon joint loading are mediated by cells within the joint, and that these changes may be used as quantitative indicators for the intensity and duration of acute joint loading, and might serve as a powerful clinical tool to assess the effectiveness of rehabilitation and prevention exercise programs.Item Open Access Residual Force Enhancement Following Eccentric Contractions: A New Mechanism Involving Titin(American Physiology Society, 2016-01) Herzog, Walter; Schappacher, G.; DuVall, Michael M.; Leonard, Timothy R.; Herzog, Jens A.Eccentric muscle properties are not well characterized by the current paradigm of the molecular mechanism of contraction: the cross-bridge theory. Findings of force contributions by passive structural elements a decade ago paved the way for a new theory. Here, we present experimental evidence and theoretical support for the idea that the structural protein titin contributes to active force production, thereby explaining many of the unresolved properties of eccentric muscle contraction.Item Open Access The three filament model of skeletal muscle stability and force production(Tech Science Press, 2012-01) Herzog, Walter; Leonard, Timothy R.; Joumaa, Venus; DuVall, Michael M.; Panchangam, AppajiEver since the 1950s, muscle force regulation has been associated with the cross-bridge interactions between the two contractile filaments, actin and myosin. This gave rise to what is referred to as the "two-filament sarcomere model". This model does not predict eccentric muscle contractions well, produces instability of myosin alignment and force production on the descending limb of the force-length relationship, and cannot account for the vastly decreased ATP requirements of actively stretched muscles. Over the past decade, we and others, identified that a third myofilament, titin, plays an important role in stabilizing the sarcomere and the myosin filament. Here, we demonstrate additionally how titin is an active participant in muscle force regulation by changing its stiffness in an activation/force dependent manner and by binding to actin, thereby adjusting its free spring length. Therefore, we propose that skeletal muscle force regulation is based on a three filament model that includes titin, rather than a two filament model consisting only of actin and myosin filaments consisting only of actin and myosin filaments