Shortening velocity and other manifestations of muscle dynamics
- Bronchospasm and its biophysical basis in airway smooth muscle
The oldest and certainly the simplest explanation of airway hyperreactivity would be that muscle from the asthmatic airway is stronger than muscle from the healthy airway, but evidence in support of that hypothesis remains equivocal [3,4,88]. Indeed, studies from the laboratory of Stephens and colleagues [26,89-91] have emphasized that the force generation capacity of allergen-sensitized airway smooth muscle of the dog, or asthmatic muscle from the human, is no different from that of control muscle. As a result, the search for an explanation turned to other factors, and several alternative hypotheses have been advanced. These fall into three broad classes, each of which is consistent with remodeling events induced by the inflammatory microenvironment, and include an increase of muscle mass [13,77,92], a decrease of the static load against which the muscle shortens [13,75,77,92], and a decrease of the fluctuating load that perturbs myosin binding during breathing, described in greater detail below [23,24,93,94]. Aside from their effects on acto-myosin binding, changes in the static load and/or the dynamic load also lead to dramatic cytoskeletal remodeling events as the smooth muscle cell adapts to its microenvironment. Together, these hypotheses are attractive because they suggest a variety of mechanisms by which airway smooth muscle can shorten excessively even while the isometric force generating capacity of the muscle remains essentially unchanged.
Setting the muscle length: a process equilibrated statically or dynamically?
Even if the force generating capacity is unchanged, a consistent association has been noted between airway hyperresponsiveness and unloaded shortening velocity of the muscle [89,90,95-97]. This association suggests the possibility that the problem with airway smooth muscle in asthma may be that it is too fast rather than too strong. But how shortening velocity – a dynamic property of the muscle – might cause excessive airway narrowing – a parameter that was thought to be determined by a balance of static forces – remains unclear. To account for increased shortening capacity of unloaded cells, Stephens and colleagues have reasoned that upon activation virtually all muscle shortening is completed within the first few seconds . As such, the faster the muscle can shorten within this limited time window, the more it will shorten. However, in isotonic loading conditions at physiological levels of load, muscle shortening is indeed most rapid at the very beginning of the contraction, but appreciable shortening continues for at least 10 min after the onset of the contractile stimulus . An alternative hypothesis to explain why intrinsically faster muscle might shorten more comes from consideration of the temporal fluctuations of the muscle load that are attributable to the action of spontaneous breathing [24,88,98]}. Load fluctuations that are attendant to spontaneous breathing are the most potent of all known bronchodilating agencies [99,100]. Among many possible effects, these load fluctuations perturb the binding of myosin to actin, causing the myosin head to detach from actin much sooner than it would have during an isometric contraction. But the faster the myosin cycling (i.e., the faster the muscle), the more difficult it is for imposed load fluctuations to perturb the actomyosin reaction. This is because the faster the intrinsic rate of cycling, the faster will a bridge, once becoming detached, reattach and contribute once again to active force and stiffness.
Why is muscle from the allergen sensitized animal or asthmatic subject faster? For technical reasons, in their study on biopsy specimens from asthmatic subjects Ma et al  did not measure expression of myosin light chain kinase, but their finding of increased content of message strongly implicates MLCK. Although regulation of myosin phosphorylation is a complex process with multiple kinase and phosphatase pathways, this finding substantially narrows the search for the culprit that may account for the mechanical changes observed in these cells. Also, these studies seem to rule out changes in the distribution of myosin heavy chain isoforms; content and isoform distributions of message from asthmatic cells showed the presence of smooth muscle myosin heavy chain A (SM-A) but not SM-B, the latter of which contains a seven-amino acid insert, is typical of phasic rather than tonic smooth muscle, and is by far the faster of the two isoforms [101,102]. Together, these findings confirm in muscle biopsy specimens from the asthmatic airway a number of findings from the allergen-sensitized dog model.
Cycling rate regulation
In smooth muscle, shortening velocity and its determinants are of particular interest [60,103]. Compared to striated muscle, the maximum unloaded shortening velocity of smooth muscle is smaller by more than an order of magnitude. This difference seems to be a adaptation to smooth muscle functions; whereas striated muscles typically produce motion or work in an efficient manner (i.e., converting chemical energy into mechanical energy with a small amount of energy lost to heat), smooth muscles are found in hollow organs where they serve to maintain tone or shape in an economical manner (i.e., doing so at a rate of chemical energy utilization that is smaller than that consumed striated muscle by about 300 fold [59,60]. Since the rate of myosin ATPase activity is tied directly to the myosin cyclic rate [104,105], a slower cycling rate implies economical maintenance of tone.
If smooth muscle is activated but held isometrically as the waiting time between the stimulus onset and a subsequent quick release is increased, the isometric force grows but the rate of ATP utilization and unloaded shortening velocity immediately after the release progressively decrease; this curious behavior represents a major distinction between smooth and striated muscle. Huxley's view of muscle contraction implies that the unloaded shortening velocity is set by the rate at which the myosin head can advance along the actin filament. Accordingly, for a given myosin step size, this means that shortening velocity is a direct measure of cross bridge cycling rate. Since the shortening velocity is found to decrease appreciably with increasing waiting time, the logical explanation following these ideas is that the cycling rate is a regulated variable and decreases as a function of time since the onset of the activation. Taken together, force maintenance, down-regulation of unloaded shortening velocity, and reduced rates of ATP utilization, comprise what is known as the latch state, or, equivalently, the latch phenomenon.
Force generated by any smooth muscle is sustained by cyclic interactions of myosin with actin. With onset of the contractile event, myosin-actin cycling begins and the number of interactions (bridges) increases and eventually approaches a steady state. It is widely agreed that during this process the rate of bridge cycling initially increases but then becomes substantially diminished. The mechanisms of cycling rate regulation remain very much an open question in the literature [103,106-113].
Among mechanisms of cycling rate regulation that have been proposed, the foremost is the latch hypothesis of Hai and Murphy, which has the attributes of being the simplest and capturing the central importance of phosphorylation of the 20 kDa myosin regulatory light chain [103,106,114-116]. Murphy and his colleagues suggested that the latch phenomenon arises as rapidly cycling cross bridges are replaced progressively by slowly cycling latch bridges if given enough time at a fixed muscle length, where the latch bridge is nothing more than a myosin head whose 20 kDa regulatory light chain becomes dephosphorylated while remaining attached to actin and maintaining both force and stiffness. The central notion is that the latch bridge has a very small rate of detachment from actin and, as a result, the latch bridge comprises an internal load against which rapidly cycling bridges must shorten .
Within the latch schema, the attainment of the isometric steady state implies that the population distribution of myosin molecules among their four possible states (attached vs. unattached to actin, phosphorylated vs. unphosphorylated regulatory light chains) have come to a binding equilibrium set by a balance of kinetic rate processes, many of which are ATP dependent. Once enough time has passed that this balance is attained and myosin has come to a binding equilibrium appropriate to isometric steady-state conditions, the muscle is then said to be in the latch state. Thus, the latch state corresponds to what I will refer to as a static equilibrium of myosin binding at the molecular level, and a balance of static forces at the mechanical level.
Whether the latch bridge might account for the latch phenomenon remains a point of some contention, however. The accessory proteins calponin and caldesmon are known to modulate the rate of muscle shortening, and have been suggested as being molecules responsible for or contributing to the latch phenomenon, but the mechanisms of action of these molecules are not well understood [108,117-119]. Finally, if contractile units were evanescent and the number of such units in series were to decrease progressively during a contractile event, as discussed below, it has been suggested that these adaptations might account for the latch phenomenon .
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