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Force enhancement following an active stretch in skeletal muscle
Journal of Electromyography and Kinesiology 12 (2002) 471–477 www.elsevier.com/locate/jelekin
Force enhancement following an active stretch in skeletal muscle Dilson E. Rassier, Walter Herzog ∗ Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, 2500 University Drive, Calgary (AB), Canada T2N 1N4
Abstract When skeletal muscle is stretched during a tetanic contraction, the resulting force is greater than the purely isometric force obtained at the corresponding final length. Several mechanisms have been proposed to explain this phenomenon, but the most accepted mechanism is the sarcomere length non-uniformity theory. This theory is associated with the notion of instability of sarcomeres on the descending limb of the force–length relationship. However, recent evidence suggests that this theory cannot account solely for the stretch-induced force enhancement. Some of this evidence is presented in this paper, and a new mechanism for force enhancement is proposed: one that is associated with the engagement of a passive force during stretch. We speculate that this passive force enhancement may be caused by titin, a protein associated with passive force production at long sarcomere lengths. 2002 Elsevier Science Ltd. All rights reserved. Keywords: Active force; Passive force; Sarcomeres; Stability; Force-length relation; Titin
1. Introduction It has been known for a long time that when skeletal muscle is stretched during a tetanic contraction, the force following the stretch is greater than the purely isometric force obtained at the corresponding final length [1,2]. This phenomenon has been observed in single muscle cells [3–7], whole muscles [8,9], and human muscles that are electrically stimulated [10] or contracted voluntarily [11]. The force enhancement observed after active stretch cannot be readily explained by the original cross-bridge theory of muscle contraction, as the theory does not incorporate history-dependent effects of force production [12,13]. Also, it cannot be predicted by the degree of thick and thin filament overlap [14], as isometric force following stretch at a small average overlap between myofilaments might be greater than the isometric force at a great average myofilament overlap (Fig. 1) [5]. Therefore, much research has focused on the pursuit of understanding the mechanisms of the stretch-induced force enhancement. Several mechanisms have been proposed to explain
Corresponding author. Tel.: +1-403-220-8525; fax: +1-403-2843553. E-mail address: [email protected] (W. Herzog). ∗
Fig. 1. Schematic representation of the isometric force–length relationship, and force enhancement after an active stretch. During isometric contractions, force follows the lines in the graph according to the degree of length in which the contraction starts and the degree of filament overlap. However, if the muscle is actively stretched during a contraction, e.g. from the initial to the final length (䊊), the force produced (쎲) is higher than the purely isometric force produced at the final length. Therefore, the degree of filament overlap is reduced, but the force is increased.
the stretch-induced force enhancement, including crossbridge kinetics [15], lattice spacing changes with reordering of thick and thin filaments [16], non-uniformity and instability of sarcomeres [17,18] associated with the engagement of parallel passive elements [6], and the role of titin and nebulin as additional force producers [6,19]. While some of these mechanisms have not been carefully tested, the hypothesis that incorporates non-uni-
1050-6411/02/$ - see front matter. 2002 Elsevier Science Ltd. All rights reserved. PII: S 1 0 5 0 - 6 4 1 1 ( 0 2 ) 0 0 0 4 1 - X
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formity of length and instability of sarcomeres [17,18,20] has been the most accepted theory. However, some characteristics of force enhancement following stretch, together with new experimental findings, suggest that the mechanisms of force enhancement may involve components other than non-uniformity of sarcomere length. The main purpose of this paper is to review the general characteristics of stretch-induced force enhancement, to critically evaluate proposed mechanisms of force enhancement, including the sarcomere length nonuniformity theory, and to present evidence for an alternative mechanism that may explain part of the stretchinduced force enhancement. It is expected that this review will motivate new studies on the mechanisms responsible for the stretch-induced force enhancement observed in skeletal muscle. 2. Characteristics of force enhancement after stretch The basic features of force enhancement observed after stretch are shown in Fig. 2. The muscle is first tetanized at a given sarcomere/muscle length, and after the muscle reaches maximal isometric force, it is stretched to a new length. The force produced at this new length is greater than the purely isometric force at the corresponding muscle length. Therefore, two contractions at the same muscle (fiber, average sarcomere) length result in different force, depending on whether the muscle was actively stretched during contraction, or not (Fig. 1). Force enhancement has two components: (1) a sudden increase in force that is observed during the stretch and that dissipates gradually after the stretch is finished; and (2) a stable residual increase in force that remains constant until the end of the contraction [5,6]. This second component will be called force enhancement after stretch [15]. The first component of force enhancement is well understood, and is related to the negative part of the force–velocity relationship [21]; that is, force increases with higher speeds of stretch (Fig. 2B) [4,20]. This component has been explained by an increased number of attached cross-bridges during the stretch [7], and by an increased strain of cross-bridges when sarcomeres are forcibly extended during a tetanic contraction [22]. Therefore, force enhancement during stretch has been associated with regular cross-bridge properties, as described in the cross-bridge theory [12]. Force enhancement after stretch has characteristics that seem unrelated to cross-bridge properties. Most notably, the force is enhanced (compared to the purely isometric force and compared to the force predicted by the average overlap of filaments) during the entire period during which the fiber is activated. In this paper, we will concentrate on the characteristics and proposed mechanisms of the residual force enhancement after stretch.
Fig. 2. Stretch-induced force enhancement observed during a typical experiment performed with a single muscle fiber from the frog on the descending limb of the force–length relationship. (A) shows contractions in which the fiber was stretched 5, 10 and 15% from an initial length (Li) on the descending limb of the force–length relationship, at a speed of 0.8 mm/s. It also shows an isometric contraction (Lf) performed at a length 15% greater than Li. (B) shows contractions in which the fiber was stretched 15% from Li on the descending limb of the force–length relationship, at speeds of 0.4, 0.8 and 2.0 mm/s, and an isometric contraction (Lf) performed at a length 15% greater than Li. Force enhancement increases with the amplitude of stretch but is independent of the speed of stretch.
The enhanced force observed after stretch is stable at 苲4.5 s following the length change [5,6]. The amount of force enhancement depends on the amplitude of stretch (Fig. 2A), but is independent (or at least nearly so) of the speed of stretch (Fig. 2B). Increasing stretch amplitude results in greater force enhancement [1,4,5,23]. Exceptions to these findings are the studies by Julian and Morgan [20] and Morgan et al. [9], in which the level of force enhancement was interpreted to be independent of the amplitude of stretch. The degree of force enhancement after stretch depends on the initial sarcomere length from which the muscle is stretched. It has been shown that, along the descending limb of the force–length relationship, force enhancement is increased when the muscle fiber is stretched from greater muscle lengths [5]. Most studies on force enhancement were performed on the descending limb of the force–length relationship, and it has been suggested
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that force enhancement is observed only in this region [4,5,20]. However, little effort has been made to evaluate force enhancement on the ascending limb of the force– length relationship. Recent studies show steady-state force enhancement following active muscle stretch on the ascending limb of the force–length relationship (later in this paper). Using whole cat soleus, Herzog and Leonard [24] observed that muscle shortening that immediately preceded stretching affected the amount of force enhancement. More precisely, they observed that for a given stretch (speed, amplitude), force enhancement was decreased in a dose-dependent manner with the amount of shortening preceding the stretch. However, in experiments with single cells from the frog, Edman et al. [5] found that force enhancement was not affected by shortening that preceded stretching, when a brief pause was given between the length changes. This difference between the two studies is conspicuous, and it may be caused by the preparations (whole muscle vs single cells), or by the protocols (with and without pauses between shortening and stretching phases). Julian and Morgan [20] showed that an interruption of the contraction introduced after the stretch changes the enhanced force in a time-dependent manner, such that a short interruption does not abolish force enhancement, but a long interruption eliminates all force enhancement. Future research is needed to better understand how force enhancement is affected by shortening preceding the stretching phase. An important feature of force enhancement after stretch that still needs to be carefully investigated is its association (or not) with an increased stiffness, as contradictory results exist in the literature. Assuming that stiffness is directly related to the number of crossbridges attached to actin [25,26], an increased stiffness in the force-enhanced state could be related to a higher number of attached cross-bridges after stretch. Sugi and Tsuchiya [23] performed a series of experiments in which they measured fiber stiffness by applying sinusoidal vibrations to the cells during isometric contractions and stretch contractions. It was observed that, although the force was increased (as expected) after the stretch, the stiffness was the same as observed during isometric contractions produced at that final length. However, Linari et al. [7] observed an increased stiffness in single muscle cells just after stretch, which was directly associated with an increased force enhancement. It should be cautioned that in their experiments force never reached a steady-state condition, as contractions were very short (1–3 s). In order to evaluate their results critically in terms of steady-state force enhancement, experiments with longer contraction times should be performed.
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3. Mechanisms of force enhancement after stretch Force enhancement after stretch has been related to an increased number of attached cross-bridges, to changes in the cross-bridge dynamics, or to some noncross-bridge sarcomeric properties. A mechanism associated with the cross-bridge dynamics would have to assume an increased average force per attached crossbridge [15]. A mechanism associated with non-crossbridge properties may be associated with sarcomere mechanics and/or the involvement of sarcomeric proteins, independent of the proportion of attached crossbridges. A hypothesis related to the cross-bridge dynamics was introduced by Amemiya et al. [16]. These authors used X-ray diffraction to measure filament position after stretch, and observed a disordering of the myofilament lattice without significant changes in the mean interfilament spacing. This disordering was characterized as a displacement of the thin filaments from their initial position to a position closer to the thick filaments. This arrangement persisted while the muscle was stimulated. Such a decrease in lattice spacing could enhance the probability of cross-bridge attachment, and consequently force generation. Although it is difficult to directly evaluate the mechanism proposed by Amemya et al. [16], a similar result is observed when a twitch contraction is potentiated by phosphorylation of the myosin regulatory light chains. In this case, myosin phosphorylation moves the crossbridges towards the thin filament [27]. This approximation of the cross-bridge heads to potential actin attachment sites is believed to increase the probability of myosin/actin interactions, and consequently force generation at a given sub-maximal Ca2+ concentration [28]. Due to the difficulty of testing cross-bridge hypotheses experimentally, they should be considered in theoretical models, in which force production can be simulated using cross-bridges with different rates of attachment/detachment before and after stretch. Another possibility is that the level of phosphorylation of the regulatory light chains is enhanced during stretch, as suggested by Edman [3]. Since the rate constant for dephosphorylation of the light chains is very slow, myosin would remain phosphorylated after muscle stretching, and could produce the long lasting force enhancement following stretching. However, there is no evidence that an active stretch enhances the biochemical steps involved in myosin light chain phosphorylation, (e.g. enhancement of the myosin light chain kinase activity), but this hypothesis should be tested in the near future. 4. The theory of sarcomere length non-uniformity The mechanism of force enhancement after stretch that has received more attention in the scientific com-
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munity than any other mechanism is the sarcomere length non-uniformity theory [20]. This idea has been used by several researchers [6,9] and was ultimately associated with the ‘popping sarcomeres’ theory [18]. The first experimental observation related to the sarcomere length non-uniformity theory was made by Julian and Morgan [20]. They observed that during stretch of single cells, sarcomere lengths did not change by the same amount: sarcomeres near the center of the cells stretched more than average, while sarcomeres near the end of the cell stretched less than average. Julian and Morgan [20] suggested that this non-uniformity of sarcomere lengths was responsible for the force enhancement after stretch. However, in a subsequent study, Edman et al. [5] observed that force enhancement was not only produced by muscle fibers as a whole, but also by individual clamped segments of the fiber, and by isolated sarcomere populations. Edman et al. [5] concluded that force enhancement was possible, independently of the development of sarcomere length non-uniformity. Morgan [18] incorporated observations of sarcomere length non-uniformity [20] and sarcomere instability on the descending limb of the force–length relationship [17] to provide an explanation for the force enhancement after stretch. Morgan [18] argued that when fibers are actively stretched on the descending limb of the force– length relationship, sarcomeres located near the center of the fiber are stretched more than sarcomeres near the end of the fiber. As the stretch continues, these sarcomeres are stretched until actin–myosin overlap is lost (i.e. they ‘pop’). Sarcomeres located near the end of the fibers do not stretch as much, and may in fact stay almost isometric during the elongation of the cell. These sarcomeres produce the active force in the fiber. The ‘popped’ sarcomeres are supported by the passive tension present on the descending limb of the force–length relationship. The two groups of sarcomeres need to have equal force to attain equilibrium. At equilibrium, the force produced by the two groups of sarcomeres is greater than the isometric force at the corresponding length, which is assumed to have a relatively uniform (average) sarcomere length distribution. The sarcomere length non-uniformity theory can explain some experimentally observed features of force enhancement after stretch.
5. Instability and non-uniformity of sarcomeres Naturally, the theory of ‘popping’ sarcomeres is based on the notion of an inherent instability of sarcomere lengths that is present on the descending limb of the force–length relationship [17,20]. Instability would be responsible for the non-uniform length changes in sarcomeres, which in turn causes sarcomere dispersion and heterogeneity in sarcomere lengths during contractions. The notion of instability was first introduced by Hill
[29], who suggested that sarcomeres were unstable on the descending limb because of the negative slope of the force–length relationship in that region. However, the force–length relationship is obtained by isolated contractions at different lengths, e.g. Gordon et al. [14], and it is not necessarily correct to infer dynamic instability from a static observation. In fact, it is quite easy to design systems in which the static force decreases while the dynamic force increases with increasing length [30,31]. Several researchers suggested that sarcomere lengths are stable during contractions over the whole physiological range of lengths, including the descending limb of the force–length relationship [30,32–34]. It has been shown that force following stretch is, in some situations, not only greater than the isometric force obtained at the final length (as discussed previously), but also greater than the force recorded at the initial length from which the muscle was stretched [4,5]. This force enhancement above the initial isometric force can be observed after the force reaches a steady-state following stretch [35,36]. In this case, the dynamic force–length trace has a positive slope that is characteristic of a stable system that exhibits hardening properties. This idea agrees with observations that a fiber that is stretched on the descending limb of the force–length relationship has a positive stiffness during the stretch [37,38]. Along those lines, Allinger et al. [39] showed that the dispersion of sarcomere length decreases during a tetanic contraction, which is a property of a stable system. Therefore, sarcomere lengths may be stable on the descending limb of the force–length relationship, thereby questioning the origin of the popping sarcomere and the sarcomere length non-uniformity theories. Although it is difficult to directly evaluate the sarcomere length nonuniformity theory experimentally, its well-defined mathematical framework allows for the derivation of testable hypotheses. If the sarcomere length non-uniformity theory is the sole mechanism responsible for the steadystate force enhancement after stretch, and if sarcomeres behave as proposed by Morgan [18], then the following should be true: (1) force enhancement after stretch should not be observed on the ascending limb of the force–length relationship, as this region is not associated with instability of sarcomeres and the development of sarcomere length non-uniformities; and (2) force following stretch should never exceed the isometric force produced on the plateau of the force–length relationship. We performed experiments with the cat soleus and with single cells dissected from the frog, in which we tested the above hypotheses. Using single muscle cells dissected from the frog (Rana pipiens) we observed that, on the ascending limb of the force–length relationship, the steady-state force following stretch was greater than the purely isometric force produced at the final length. The amount of force
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enhancement was generally smaller on the ascending compared to the descending limb of the force–length relationship. The same observation was made in the in situ cat soleus. In these experiments, soleus was stimulated at 5 and 30 Hz, and we observed a small but consistent force enhancement on the ascending limb of the force–length relation [8]. Force enhancement on the ascending limb of the force–length relationship was also reported by De Ruiter et al. [10] in human adductor pollicis muscle. Other investigators, using single cells from frog or whole muscles from the cat, failed to find force enhancement on the ascending limb of the force–length relationship [6,9,20]. They may have used amplitudes of stretch that were too short to observe a measurable force enhancement. In another series of experiments performed with single muscle cells from frogs, we were interested in determining if force enhancement could be observed at levels above the isometric force produced on the plateau of the force–length relationship. Our interest was based on previously reported results. Edman et al. [5] (their Fig. 3), showed force enhancement of about 1–2% greater than the isometric force produced at the plateau of the force– length relationship. The authors credited the results to measurement error, and did not persist to evaluate their finding. Results from one experiment from our study are shown in Fig. 3. In this case, force following stretch exceeded the isometric force produced at the initial length, showing stable properties as explained above. Even more important for the present discussion, force after stretch also exceeded the isometric force produced at the plateau of the force–length relationship. This result was statistically confirmed in more than 30 separate experiments. In some cases, force was 苲10% higher than
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the maximal isometric force on the plateau of the force– length relationship. An unstable system, or a theory based on the sarcomere length non-uniformity idea alone, cannot explain this result. If some sarcomeres ‘pop’ during stretch, and others are maintained isometric (or stretch only by a small amount) during the stretch of the whole fiber, force cannot exceed the maximal isometric force produced at the plateau of the force– length relationship.
6. Alternative mechanism of force enhancement after stretch Since the sarcomere length non-uniformity and the popping sarcomere theory cannot account for the force enhancement above the plateau forces, other mechanisms should be considered. An alternative, or additional, mechanism of force enhancement after stretch should incorporate all the characteristics observed in the experiments described, and should assume that the muscular system is stable under contraction. One possibility that has been often mentioned in the literature but has not received direct experimental support is the idea that a passive elastic element is engaged during an active stretch [6,19]. Edman and Tsuchiya [6] performed a series of experiments in which single muscle fibers were released to shorten against a small load at different times after a stretch, and also after tetanic contractions. The force transients of the contractions in which a stretch was applied exhibited a greater and steeper decrease in force than those obtained during an isometric contraction. These findings were interpreted as resulting from the elongation of a passive elastic struc-
Fig. 3. Active and passive force enhancement observed during a typical experiment performed with a single muscle fiber from the frog on the descending limb of the force–length relationship. After stretch, active force is higher than the isometric force recorded at the initial length (Li), and is also higher than the isometric force recorded at the plateau (Lo) of the force–length relation. The passive force is greater when the stretch is performed during contraction than when the muscle is stretched passively.
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ture. The authors suggested that some half-sarcomeres would stretch more than others during the elongation, and these overstretched regions of the sarcomere would be supported by the engagement of an elastic, passive structure. Alternatively, the engagement of a passive element could be directly responsible for the increase in force. Although this possibility has not been directly tested, it has been observed that under some conditions, force enhancement is accompanied by an increase in the passive force (Fig. 3) [8]. This increase in passive force produced by stretching an active muscle is not observed when the muscle is passively stretched (Fig. 3). We refer to this phenomenon as ‘passive force enhancement’. The passive force enhancement appears to persist for as long as the muscle is not shortened, and we speculate that the passive force enhancement may account for part of the total force enhancement observed after stretch. Such a hypothesis has been shown to work in theory in a rheological muscle model that incorporated a passive component to explain the steady-state force enhancement after stretch [40]. The origin of this passive force enhancement is unknown, but based on the structure of the sarcomeres and the origin of passive force during a non-activated stretch, the protein titin seems a prime candidate. Titin connects thick filaments to the Z-line, and titin is responsible for passive force in skeletal and cardiac muscles when stretched to a great length [41,42]. If, upon activation, the increased level of myoplasmic Ca2+ somehow increases the stiffness of titin, either by binding to the protein or by changing the biochemical environment in the myoplasm, then the passive force in titin would be increased compared to a non-activated stretch. 7. Conclusions Force enhancement after stretch has been observed in a variety of skeletal muscle preparations, ranging from single muscle cells to human muscles during voluntary contractions. Although the sarcomere length non-uniformity theory has been used primarily to explain the steady-state force enhancement, the theory is based on the notion of instability of sarcomeres on the descending limb of the force–length relationship. However, there is evidence that skeletal muscle is stable on the descending limb of the force–length relationship. Furthermore, force enhancement has been observed by different research groups on the ascending limb of the force–length relationship. Finally, we have presented experimental data showing force enhancement above plateau forces in cat soleus and single fibers from the frog. Together with the demonstration of a persistent passive force enhancement following active stretch, we must conclude that the sarcomere length non-uniformity theory cannot be the sole mechanism to explain all these observations.
With the possibility of measuring force in isolated myofibrils [43], one could evaluate the behavior of each sarcomere in a myofibril during contraction. With such measurements, it should be possible to accompany the behavior of individual sarcomeres along a myofibril and investigate, at that level, if the system is unstable or stable. If such measurements were made before and after an active stretch, then the question of non-uniformity of sarcomeres in association with the force enhancement observed after stretch could be clearly answered.
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[18] Morgan DL. An explanation for residual increased tension in striated muscle after stretch during contraction. Exp Physiol 1994;79:831–8. [19] Noble MIM. Enhancement of mechanical performance of striated muscle by stretch during contraction. Exp Physiol 1992;77:539–52. [20] Julian FJ, Morgan DL. The effect on tension of non-uniformity distribution of length changes applied to frog muscle fibres. J Physiol 1979;293:379–92. [21] Katz B. The relation between force and speed in muscular contraction. J Physiol 1939;96:45–64. [22] Lombardi V, Piazzesi G. The contractile response during steady lengthening of stimulated frog muscle fibres. J Physiol 1990;431:141–71. [23] Sugi H, Tsuchiya T. Stiffness changes during enhancement and deficit of isometric force by slow length changes in frog skeletal muscle fibres. J Physiol 1988;407:215–29. [24] Herzog W, Leonard TR. The history dependence of force production in mammalian skeletal muscle following stretch-shortening and shortening-stretch cycles. J Biomech 2000;33:531–42. [25] Ford LE, Huxley AF, Simmons RM. The relation between stiffness and filament overlap in stimulated frog muscle fibres. J Physiol 1981;311:219–49. [26] Julian FJ, Sollins MR. Variation in muscle stiffness with force at increasing speeds of shortening. J Gen Physiol 1975;66:287–302. [27] Levine RJC, Kensler RW, Yang Z, Stull JT, Sweeney HL. Myosin light chain phosphorylation affects the structure of rabbit skeletal muscle thick filaments. Biophys J 1996;71:898–907. [28] Sweeney HL, Stull JT. Alteration of cross-bridge kinetics by myosin light chain phosphorylation in rabbit skeletal muscle: implications for regulation of actin-myosin interaction. Proc Natl Acad Sci USA 1990;87:414–8. [29] Hill AV. The mechanics of active muscle. Proc Royal Soc Lond B 1953;141:104–17. [30] Allinger TL, Epstein M, Herzog W. Stability of muscle fibers on the descending limb of the force-length relation. A theoretical consideration. J Biomech 1996;29:627–33. [31] Epstein M, Herzog W. Theoretical models of skeletal muscle: Biological and mathematical considerations. New York: Wiley, 1998. [32] Deleze JB. The mechanical properties of the semitendinosus muscle at lengths greater than its length in the body. J Physiol 1961;158:154–64. [33] Pollack GH. Muscles and Molecules. Seattle: Ebner, 1990. [34] ter Keurs HEDJ, Iwazumi T, Pollack GH. The sarcomere lengthtension relation in skeletal muscle. J Gen Physiol 1978;72:565– 92. [35] Schachar R, Herzog W, Leonard TR. Stability and the descending limb of the force-length relation in mammalian skeletal muscle. XI Congress of the Canadian Society for Biomechanics; 2000:148.
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[36] Wakeling J, Herzog W, Syme D. Force enhancement and stability in skeletal muscle fibers. XI Congress of the Canadian Society for Biomechanics; 2000:148. [37] Bagni MA, Cecchi G, Cecchini E, Colombini B, Colomo F. Force responses to fast ramp stretches in stimulated skeletal muscle fibres. J Muscle Res Cell Motil 1998;19:33–42. [38] Montovani M, Cavagna GA, Heglund NC. Effect of stretching on undamped elasticity in muscle fibres from Rana temporaria. J Muscle Res Cell Motil 1999;20:33–43. [39] Allinger TL, Herzog W, ter Keurs HEDJ, Epstein M. Sarcomere length non-uniformity and stability on the descending limb of the force-length relation of mouse skeletal muscle. In: Herzog W, editor. Skeletal muscle mechanics: From mechanisms to function. New York: Wiley; 2000. p. 455–74. [40] Forcinito M, Epstein M, Herzog W. Can a rheological muscle model predict force depression/enhancement? J Biomech 1998;31:1093–9. [41] Kellermayer MSZ, Smith SB, Granzier HLM, Bustamante C. Folding-unfolding transitions in single titin molecules characterized with laser tweezers. Science 1997;276:1112–6. [42] Rief M, Gautel M, Oesterhelt F, Fernandez JM, Gaub HE. Reversible unfolding of individual titin immunoglobulin domains by AFM. Science 1997;276:1109–12. [43] Bartoo ML, Popo VI, Fearn LA, Pollack GH. Active force generation in isolated skeletal myofibrils. J Muscle Res Cell Motil 1993;14:498–510. Dilson Rassier is a post-doctoral fellow under supervision of Walter Herzog, at the University of Calgary (Canada). He received his BS in Physical Education from the Federal University of Pelotas (Brazil), his MSc in Exercise Physiology from the Federal University of Rio Grande do Sul (Brazil), and his PhD in Muscle Physiology from the University of Calgary (Canada). His research examines the mechanisms of muscle contraction and force regulation. Walter Herzog is Professor of Biomechanics with Joint Appointments in Kinesiology, Engineering and Medicine at the University of Calgary. He serves as the Associate Dean for Research in Kinesiology and holds a Canadian Research Chair in Cellular and Molecular Biomechanics. He received his Bachelor’s degree from the Federal Technical Institute in Zurich, Switzerland, his Master’s/PhD degree from the University of Iowa, USA, and pursued postdoctoral training at the University of Calgary, Canada. In 1987, he accepted his current position in Calgary.
Force enhancement following an active stretch in skeletal muscle Dilson E. Rassier, Walter Herzog ∗ Human Performance Laboratory, Faculty of Kinesiology, University of Calgary, 2500 University Drive, Calgary (AB), Canada T2N 1N4
Abstract When skeletal muscle is stretched during a tetanic contraction, the resulting force is greater than the purely isometric force obtained at the corresponding final length. Several mechanisms have been proposed to explain this phenomenon, but the most accepted mechanism is the sarcomere length non-uniformity theory. This theory is associated with the notion of instability of sarcomeres on the descending limb of the force–length relationship. However, recent evidence suggests that this theory cannot account solely for the stretch-induced force enhancement. Some of this evidence is presented in this paper, and a new mechanism for force enhancement is proposed: one that is associated with the engagement of a passive force during stretch. We speculate that this passive force enhancement may be caused by titin, a protein associated with passive force production at long sarcomere lengths. 2002 Elsevier Science Ltd. All rights reserved. Keywords: Active force; Passive force; Sarcomeres; Stability; Force-length relation; Titin
1. Introduction It has been known for a long time that when skeletal muscle is stretched during a tetanic contraction, the force following the stretch is greater than the purely isometric force obtained at the corresponding final length [1,2]. This phenomenon has been observed in single muscle cells [3–7], whole muscles [8,9], and human muscles that are electrically stimulated [10] or contracted voluntarily [11]. The force enhancement observed after active stretch cannot be readily explained by the original cross-bridge theory of muscle contraction, as the theory does not incorporate history-dependent effects of force production [12,13]. Also, it cannot be predicted by the degree of thick and thin filament overlap [14], as isometric force following stretch at a small average overlap between myofilaments might be greater than the isometric force at a great average myofilament overlap (Fig. 1) [5]. Therefore, much research has focused on the pursuit of understanding the mechanisms of the stretch-induced force enhancement. Several mechanisms have been proposed to explain
Corresponding author. Tel.: +1-403-220-8525; fax: +1-403-2843553. E-mail address: [email protected] (W. Herzog). ∗
Fig. 1. Schematic representation of the isometric force–length relationship, and force enhancement after an active stretch. During isometric contractions, force follows the lines in the graph according to the degree of length in which the contraction starts and the degree of filament overlap. However, if the muscle is actively stretched during a contraction, e.g. from the initial to the final length (䊊), the force produced (쎲) is higher than the purely isometric force produced at the final length. Therefore, the degree of filament overlap is reduced, but the force is increased.
the stretch-induced force enhancement, including crossbridge kinetics [15], lattice spacing changes with reordering of thick and thin filaments [16], non-uniformity and instability of sarcomeres [17,18] associated with the engagement of parallel passive elements [6], and the role of titin and nebulin as additional force producers [6,19]. While some of these mechanisms have not been carefully tested, the hypothesis that incorporates non-uni-
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formity of length and instability of sarcomeres [17,18,20] has been the most accepted theory. However, some characteristics of force enhancement following stretch, together with new experimental findings, suggest that the mechanisms of force enhancement may involve components other than non-uniformity of sarcomere length. The main purpose of this paper is to review the general characteristics of stretch-induced force enhancement, to critically evaluate proposed mechanisms of force enhancement, including the sarcomere length nonuniformity theory, and to present evidence for an alternative mechanism that may explain part of the stretchinduced force enhancement. It is expected that this review will motivate new studies on the mechanisms responsible for the stretch-induced force enhancement observed in skeletal muscle. 2. Characteristics of force enhancement after stretch The basic features of force enhancement observed after stretch are shown in Fig. 2. The muscle is first tetanized at a given sarcomere/muscle length, and after the muscle reaches maximal isometric force, it is stretched to a new length. The force produced at this new length is greater than the purely isometric force at the corresponding muscle length. Therefore, two contractions at the same muscle (fiber, average sarcomere) length result in different force, depending on whether the muscle was actively stretched during contraction, or not (Fig. 1). Force enhancement has two components: (1) a sudden increase in force that is observed during the stretch and that dissipates gradually after the stretch is finished; and (2) a stable residual increase in force that remains constant until the end of the contraction [5,6]. This second component will be called force enhancement after stretch [15]. The first component of force enhancement is well understood, and is related to the negative part of the force–velocity relationship [21]; that is, force increases with higher speeds of stretch (Fig. 2B) [4,20]. This component has been explained by an increased number of attached cross-bridges during the stretch [7], and by an increased strain of cross-bridges when sarcomeres are forcibly extended during a tetanic contraction [22]. Therefore, force enhancement during stretch has been associated with regular cross-bridge properties, as described in the cross-bridge theory [12]. Force enhancement after stretch has characteristics that seem unrelated to cross-bridge properties. Most notably, the force is enhanced (compared to the purely isometric force and compared to the force predicted by the average overlap of filaments) during the entire period during which the fiber is activated. In this paper, we will concentrate on the characteristics and proposed mechanisms of the residual force enhancement after stretch.
Fig. 2. Stretch-induced force enhancement observed during a typical experiment performed with a single muscle fiber from the frog on the descending limb of the force–length relationship. (A) shows contractions in which the fiber was stretched 5, 10 and 15% from an initial length (Li) on the descending limb of the force–length relationship, at a speed of 0.8 mm/s. It also shows an isometric contraction (Lf) performed at a length 15% greater than Li. (B) shows contractions in which the fiber was stretched 15% from Li on the descending limb of the force–length relationship, at speeds of 0.4, 0.8 and 2.0 mm/s, and an isometric contraction (Lf) performed at a length 15% greater than Li. Force enhancement increases with the amplitude of stretch but is independent of the speed of stretch.
The enhanced force observed after stretch is stable at 苲4.5 s following the length change [5,6]. The amount of force enhancement depends on the amplitude of stretch (Fig. 2A), but is independent (or at least nearly so) of the speed of stretch (Fig. 2B). Increasing stretch amplitude results in greater force enhancement [1,4,5,23]. Exceptions to these findings are the studies by Julian and Morgan [20] and Morgan et al. [9], in which the level of force enhancement was interpreted to be independent of the amplitude of stretch. The degree of force enhancement after stretch depends on the initial sarcomere length from which the muscle is stretched. It has been shown that, along the descending limb of the force–length relationship, force enhancement is increased when the muscle fiber is stretched from greater muscle lengths [5]. Most studies on force enhancement were performed on the descending limb of the force–length relationship, and it has been suggested
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that force enhancement is observed only in this region [4,5,20]. However, little effort has been made to evaluate force enhancement on the ascending limb of the force– length relationship. Recent studies show steady-state force enhancement following active muscle stretch on the ascending limb of the force–length relationship (later in this paper). Using whole cat soleus, Herzog and Leonard [24] observed that muscle shortening that immediately preceded stretching affected the amount of force enhancement. More precisely, they observed that for a given stretch (speed, amplitude), force enhancement was decreased in a dose-dependent manner with the amount of shortening preceding the stretch. However, in experiments with single cells from the frog, Edman et al. [5] found that force enhancement was not affected by shortening that preceded stretching, when a brief pause was given between the length changes. This difference between the two studies is conspicuous, and it may be caused by the preparations (whole muscle vs single cells), or by the protocols (with and without pauses between shortening and stretching phases). Julian and Morgan [20] showed that an interruption of the contraction introduced after the stretch changes the enhanced force in a time-dependent manner, such that a short interruption does not abolish force enhancement, but a long interruption eliminates all force enhancement. Future research is needed to better understand how force enhancement is affected by shortening preceding the stretching phase. An important feature of force enhancement after stretch that still needs to be carefully investigated is its association (or not) with an increased stiffness, as contradictory results exist in the literature. Assuming that stiffness is directly related to the number of crossbridges attached to actin [25,26], an increased stiffness in the force-enhanced state could be related to a higher number of attached cross-bridges after stretch. Sugi and Tsuchiya [23] performed a series of experiments in which they measured fiber stiffness by applying sinusoidal vibrations to the cells during isometric contractions and stretch contractions. It was observed that, although the force was increased (as expected) after the stretch, the stiffness was the same as observed during isometric contractions produced at that final length. However, Linari et al. [7] observed an increased stiffness in single muscle cells just after stretch, which was directly associated with an increased force enhancement. It should be cautioned that in their experiments force never reached a steady-state condition, as contractions were very short (1–3 s). In order to evaluate their results critically in terms of steady-state force enhancement, experiments with longer contraction times should be performed.
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3. Mechanisms of force enhancement after stretch Force enhancement after stretch has been related to an increased number of attached cross-bridges, to changes in the cross-bridge dynamics, or to some noncross-bridge sarcomeric properties. A mechanism associated with the cross-bridge dynamics would have to assume an increased average force per attached crossbridge [15]. A mechanism associated with non-crossbridge properties may be associated with sarcomere mechanics and/or the involvement of sarcomeric proteins, independent of the proportion of attached crossbridges. A hypothesis related to the cross-bridge dynamics was introduced by Amemiya et al. [16]. These authors used X-ray diffraction to measure filament position after stretch, and observed a disordering of the myofilament lattice without significant changes in the mean interfilament spacing. This disordering was characterized as a displacement of the thin filaments from their initial position to a position closer to the thick filaments. This arrangement persisted while the muscle was stimulated. Such a decrease in lattice spacing could enhance the probability of cross-bridge attachment, and consequently force generation. Although it is difficult to directly evaluate the mechanism proposed by Amemya et al. [16], a similar result is observed when a twitch contraction is potentiated by phosphorylation of the myosin regulatory light chains. In this case, myosin phosphorylation moves the crossbridges towards the thin filament [27]. This approximation of the cross-bridge heads to potential actin attachment sites is believed to increase the probability of myosin/actin interactions, and consequently force generation at a given sub-maximal Ca2+ concentration [28]. Due to the difficulty of testing cross-bridge hypotheses experimentally, they should be considered in theoretical models, in which force production can be simulated using cross-bridges with different rates of attachment/detachment before and after stretch. Another possibility is that the level of phosphorylation of the regulatory light chains is enhanced during stretch, as suggested by Edman [3]. Since the rate constant for dephosphorylation of the light chains is very slow, myosin would remain phosphorylated after muscle stretching, and could produce the long lasting force enhancement following stretching. However, there is no evidence that an active stretch enhances the biochemical steps involved in myosin light chain phosphorylation, (e.g. enhancement of the myosin light chain kinase activity), but this hypothesis should be tested in the near future. 4. The theory of sarcomere length non-uniformity The mechanism of force enhancement after stretch that has received more attention in the scientific com-
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munity than any other mechanism is the sarcomere length non-uniformity theory [20]. This idea has been used by several researchers [6,9] and was ultimately associated with the ‘popping sarcomeres’ theory [18]. The first experimental observation related to the sarcomere length non-uniformity theory was made by Julian and Morgan [20]. They observed that during stretch of single cells, sarcomere lengths did not change by the same amount: sarcomeres near the center of the cells stretched more than average, while sarcomeres near the end of the cell stretched less than average. Julian and Morgan [20] suggested that this non-uniformity of sarcomere lengths was responsible for the force enhancement after stretch. However, in a subsequent study, Edman et al. [5] observed that force enhancement was not only produced by muscle fibers as a whole, but also by individual clamped segments of the fiber, and by isolated sarcomere populations. Edman et al. [5] concluded that force enhancement was possible, independently of the development of sarcomere length non-uniformity. Morgan [18] incorporated observations of sarcomere length non-uniformity [20] and sarcomere instability on the descending limb of the force–length relationship [17] to provide an explanation for the force enhancement after stretch. Morgan [18] argued that when fibers are actively stretched on the descending limb of the force– length relationship, sarcomeres located near the center of the fiber are stretched more than sarcomeres near the end of the fiber. As the stretch continues, these sarcomeres are stretched until actin–myosin overlap is lost (i.e. they ‘pop’). Sarcomeres located near the end of the fibers do not stretch as much, and may in fact stay almost isometric during the elongation of the cell. These sarcomeres produce the active force in the fiber. The ‘popped’ sarcomeres are supported by the passive tension present on the descending limb of the force–length relationship. The two groups of sarcomeres need to have equal force to attain equilibrium. At equilibrium, the force produced by the two groups of sarcomeres is greater than the isometric force at the corresponding length, which is assumed to have a relatively uniform (average) sarcomere length distribution. The sarcomere length non-uniformity theory can explain some experimentally observed features of force enhancement after stretch.
5. Instability and non-uniformity of sarcomeres Naturally, the theory of ‘popping’ sarcomeres is based on the notion of an inherent instability of sarcomere lengths that is present on the descending limb of the force–length relationship [17,20]. Instability would be responsible for the non-uniform length changes in sarcomeres, which in turn causes sarcomere dispersion and heterogeneity in sarcomere lengths during contractions. The notion of instability was first introduced by Hill
[29], who suggested that sarcomeres were unstable on the descending limb because of the negative slope of the force–length relationship in that region. However, the force–length relationship is obtained by isolated contractions at different lengths, e.g. Gordon et al. [14], and it is not necessarily correct to infer dynamic instability from a static observation. In fact, it is quite easy to design systems in which the static force decreases while the dynamic force increases with increasing length [30,31]. Several researchers suggested that sarcomere lengths are stable during contractions over the whole physiological range of lengths, including the descending limb of the force–length relationship [30,32–34]. It has been shown that force following stretch is, in some situations, not only greater than the isometric force obtained at the final length (as discussed previously), but also greater than the force recorded at the initial length from which the muscle was stretched [4,5]. This force enhancement above the initial isometric force can be observed after the force reaches a steady-state following stretch [35,36]. In this case, the dynamic force–length trace has a positive slope that is characteristic of a stable system that exhibits hardening properties. This idea agrees with observations that a fiber that is stretched on the descending limb of the force–length relationship has a positive stiffness during the stretch [37,38]. Along those lines, Allinger et al. [39] showed that the dispersion of sarcomere length decreases during a tetanic contraction, which is a property of a stable system. Therefore, sarcomere lengths may be stable on the descending limb of the force–length relationship, thereby questioning the origin of the popping sarcomere and the sarcomere length non-uniformity theories. Although it is difficult to directly evaluate the sarcomere length nonuniformity theory experimentally, its well-defined mathematical framework allows for the derivation of testable hypotheses. If the sarcomere length non-uniformity theory is the sole mechanism responsible for the steadystate force enhancement after stretch, and if sarcomeres behave as proposed by Morgan [18], then the following should be true: (1) force enhancement after stretch should not be observed on the ascending limb of the force–length relationship, as this region is not associated with instability of sarcomeres and the development of sarcomere length non-uniformities; and (2) force following stretch should never exceed the isometric force produced on the plateau of the force–length relationship. We performed experiments with the cat soleus and with single cells dissected from the frog, in which we tested the above hypotheses. Using single muscle cells dissected from the frog (Rana pipiens) we observed that, on the ascending limb of the force–length relationship, the steady-state force following stretch was greater than the purely isometric force produced at the final length. The amount of force
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enhancement was generally smaller on the ascending compared to the descending limb of the force–length relationship. The same observation was made in the in situ cat soleus. In these experiments, soleus was stimulated at 5 and 30 Hz, and we observed a small but consistent force enhancement on the ascending limb of the force–length relation [8]. Force enhancement on the ascending limb of the force–length relationship was also reported by De Ruiter et al. [10] in human adductor pollicis muscle. Other investigators, using single cells from frog or whole muscles from the cat, failed to find force enhancement on the ascending limb of the force–length relationship [6,9,20]. They may have used amplitudes of stretch that were too short to observe a measurable force enhancement. In another series of experiments performed with single muscle cells from frogs, we were interested in determining if force enhancement could be observed at levels above the isometric force produced on the plateau of the force–length relationship. Our interest was based on previously reported results. Edman et al. [5] (their Fig. 3), showed force enhancement of about 1–2% greater than the isometric force produced at the plateau of the force– length relationship. The authors credited the results to measurement error, and did not persist to evaluate their finding. Results from one experiment from our study are shown in Fig. 3. In this case, force following stretch exceeded the isometric force produced at the initial length, showing stable properties as explained above. Even more important for the present discussion, force after stretch also exceeded the isometric force produced at the plateau of the force–length relationship. This result was statistically confirmed in more than 30 separate experiments. In some cases, force was 苲10% higher than
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the maximal isometric force on the plateau of the force– length relationship. An unstable system, or a theory based on the sarcomere length non-uniformity idea alone, cannot explain this result. If some sarcomeres ‘pop’ during stretch, and others are maintained isometric (or stretch only by a small amount) during the stretch of the whole fiber, force cannot exceed the maximal isometric force produced at the plateau of the force– length relationship.
6. Alternative mechanism of force enhancement after stretch Since the sarcomere length non-uniformity and the popping sarcomere theory cannot account for the force enhancement above the plateau forces, other mechanisms should be considered. An alternative, or additional, mechanism of force enhancement after stretch should incorporate all the characteristics observed in the experiments described, and should assume that the muscular system is stable under contraction. One possibility that has been often mentioned in the literature but has not received direct experimental support is the idea that a passive elastic element is engaged during an active stretch [6,19]. Edman and Tsuchiya [6] performed a series of experiments in which single muscle fibers were released to shorten against a small load at different times after a stretch, and also after tetanic contractions. The force transients of the contractions in which a stretch was applied exhibited a greater and steeper decrease in force than those obtained during an isometric contraction. These findings were interpreted as resulting from the elongation of a passive elastic struc-
Fig. 3. Active and passive force enhancement observed during a typical experiment performed with a single muscle fiber from the frog on the descending limb of the force–length relationship. After stretch, active force is higher than the isometric force recorded at the initial length (Li), and is also higher than the isometric force recorded at the plateau (Lo) of the force–length relation. The passive force is greater when the stretch is performed during contraction than when the muscle is stretched passively.
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ture. The authors suggested that some half-sarcomeres would stretch more than others during the elongation, and these overstretched regions of the sarcomere would be supported by the engagement of an elastic, passive structure. Alternatively, the engagement of a passive element could be directly responsible for the increase in force. Although this possibility has not been directly tested, it has been observed that under some conditions, force enhancement is accompanied by an increase in the passive force (Fig. 3) [8]. This increase in passive force produced by stretching an active muscle is not observed when the muscle is passively stretched (Fig. 3). We refer to this phenomenon as ‘passive force enhancement’. The passive force enhancement appears to persist for as long as the muscle is not shortened, and we speculate that the passive force enhancement may account for part of the total force enhancement observed after stretch. Such a hypothesis has been shown to work in theory in a rheological muscle model that incorporated a passive component to explain the steady-state force enhancement after stretch [40]. The origin of this passive force enhancement is unknown, but based on the structure of the sarcomeres and the origin of passive force during a non-activated stretch, the protein titin seems a prime candidate. Titin connects thick filaments to the Z-line, and titin is responsible for passive force in skeletal and cardiac muscles when stretched to a great length [41,42]. If, upon activation, the increased level of myoplasmic Ca2+ somehow increases the stiffness of titin, either by binding to the protein or by changing the biochemical environment in the myoplasm, then the passive force in titin would be increased compared to a non-activated stretch. 7. Conclusions Force enhancement after stretch has been observed in a variety of skeletal muscle preparations, ranging from single muscle cells to human muscles during voluntary contractions. Although the sarcomere length non-uniformity theory has been used primarily to explain the steady-state force enhancement, the theory is based on the notion of instability of sarcomeres on the descending limb of the force–length relationship. However, there is evidence that skeletal muscle is stable on the descending limb of the force–length relationship. Furthermore, force enhancement has been observed by different research groups on the ascending limb of the force–length relationship. Finally, we have presented experimental data showing force enhancement above plateau forces in cat soleus and single fibers from the frog. Together with the demonstration of a persistent passive force enhancement following active stretch, we must conclude that the sarcomere length non-uniformity theory cannot be the sole mechanism to explain all these observations.
With the possibility of measuring force in isolated myofibrils [43], one could evaluate the behavior of each sarcomere in a myofibril during contraction. With such measurements, it should be possible to accompany the behavior of individual sarcomeres along a myofibril and investigate, at that level, if the system is unstable or stable. If such measurements were made before and after an active stretch, then the question of non-uniformity of sarcomeres in association with the force enhancement observed after stretch could be clearly answered.
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[36] Wakeling J, Herzog W, Syme D. Force enhancement and stability in skeletal muscle fibers. XI Congress of the Canadian Society for Biomechanics; 2000:148. [37] Bagni MA, Cecchi G, Cecchini E, Colombini B, Colomo F. Force responses to fast ramp stretches in stimulated skeletal muscle fibres. J Muscle Res Cell Motil 1998;19:33–42. [38] Montovani M, Cavagna GA, Heglund NC. Effect of stretching on undamped elasticity in muscle fibres from Rana temporaria. J Muscle Res Cell Motil 1999;20:33–43. [39] Allinger TL, Herzog W, ter Keurs HEDJ, Epstein M. Sarcomere length non-uniformity and stability on the descending limb of the force-length relation of mouse skeletal muscle. In: Herzog W, editor. Skeletal muscle mechanics: From mechanisms to function. New York: Wiley; 2000. p. 455–74. [40] Forcinito M, Epstein M, Herzog W. Can a rheological muscle model predict force depression/enhancement? J Biomech 1998;31:1093–9. [41] Kellermayer MSZ, Smith SB, Granzier HLM, Bustamante C. Folding-unfolding transitions in single titin molecules characterized with laser tweezers. Science 1997;276:1112–6. [42] Rief M, Gautel M, Oesterhelt F, Fernandez JM, Gaub HE. Reversible unfolding of individual titin immunoglobulin domains by AFM. Science 1997;276:1109–12. [43] Bartoo ML, Popo VI, Fearn LA, Pollack GH. Active force generation in isolated skeletal myofibrils. J Muscle Res Cell Motil 1993;14:498–510. Dilson Rassier is a post-doctoral fellow under supervision of Walter Herzog, at the University of Calgary (Canada). He received his BS in Physical Education from the Federal University of Pelotas (Brazil), his MSc in Exercise Physiology from the Federal University of Rio Grande do Sul (Brazil), and his PhD in Muscle Physiology from the University of Calgary (Canada). His research examines the mechanisms of muscle contraction and force regulation. Walter Herzog is Professor of Biomechanics with Joint Appointments in Kinesiology, Engineering and Medicine at the University of Calgary. He serves as the Associate Dean for Research in Kinesiology and holds a Canadian Research Chair in Cellular and Molecular Biomechanics. He received his Bachelor’s degree from the Federal Technical Institute in Zurich, Switzerland, his Master’s/PhD degree from the University of Iowa, USA, and pursued postdoctoral training at the University of Calgary, Canada. In 1987, he accepted his current position in Calgary.