Problem: the cross-bridge theory cannot predict history-dependent properties in general and residual force enhancement properties specifically, despite overwhelming experimental evidence and general acceptance in the scientific community that these properties exist on all structural levels of muscle.
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In the cross-bridge theory, force is exclusively produced by the interaction of actin and myosin filaments. Since interactions of actin and myosin occur in a stochastic way, the number of cross-bridges attached in the left half and right half of a sarcomere differ in general. If one half sarcomere has more cross-bridges attached than the other, it produces more force and thus will be shortening at the expense of the other half.
On the descending limb of the force-length relationship, this will result in an increased actin-myosin filament overlap zone in the half sarcomere that has shortened and less overlap in the half sarcomere that was elongated. This situation will result in an increased probability of cross-bridge attachment for the short half sarcomere compared to the long half sarcomere, thereby making the force difference between the two half sarcomeres greater.
This produces an unstable situation where one half sarcomere will end up shortened i. A similar argument for instability on the descending limb of the force-length relationship has been made for entire muscle segments [ 21 ], and for single sarcomeres [ 22 ]. However, when stretching sarcomeres in a single myofibril to lengths on the descending limb of the force-length relationship, all sarcomeres undergo a variable stretch and remain at constant, but vastly different, half- sarcomere lengths after stretch, thereby demonstrating perfectly stable properties [ 23 , 24 ] Fig.
Representative sarcomere length traces as a function of time for all individual sarcomeres of a single myofibril. The myofibril in this experiment was actively stretched from an initial average sarcomere length on the plateau of the force-length relationship to a final length on the descending limb of the force-length relationship. The cross-bridge theory, as well as the sarcomere instability theory predict that the longest weakest sarcomeres are pulled quickly beyond actin myosin filament overlap lengths greater than 3.
Therefore, there must be stabilizing elements in single, serially arranged sarcomeres in a myofibril that have not been considered in the cross-bridge theory. Problem: The cross-bridge theory predicts inherent instabilities in sarcomere and half sarcomere lengths on the descending limb of the force-length relationship, while experimentally such instabilities are not observed. In the two-filament model of the cross-bridge theory, actin and myosin are the lone active force producing elements and their interaction is based on stochastic events.
In order to produce half-sarcomere and sarcomere stability independent of sarcomere lengths, account for the experimentally observed residual force enhancement, and explain experimentally observed inconsistencies in the energetics and force trajectories in eccentric muscle contraction, a structural element connecting myosin with actin would be an elegant solution. The structural protein titin also called connectin was discovered in the mid- to lates [ 25 , 26 ], and it satisfies the above criteria. It runs across the half sarcomere inserting in the M-band of the sarcomere and connects firmly to the myosin filaments distally and actin filaments and the Z-line proximally.
In the I-band region, titin runs freely and elongates against resistance, and shortens when resistance is removed. Therefore, titin is often referred to as a molecular spring that is virtually elastic prior to the unfolding of its immunoglobulin Ig domains, but becomes highly viscous once the Ig domains are being unfolded. However, unfolding of Ig domains is thought to occur primarily at lengths greater than the normal physiological range of muscles in situ [ 27 , 28 ].
Over the past twenty years, it has been discovered that titin can change its spring stiffness in a variety of ways, for example by binding calcium and by phosphorylation of specific titin sites. Recently, there has also been evidence that proximal segments of titin might bind to actin in the presence of activation and active force production, thereby shortening its spring length, increasing its stiffness, and thus force, upon stretching [ 16 , 17 ] Fig. Evidence from single sarcomeres and myofibrils pulled to sarcomere lengths way beyond actin-myosin filament overlap while activated were associated with an increase in titin stiffness and force of up to 3—4 times of that observed by passive elongation [ 31 , 32 ] Fig.
These findings are strong evidence that titin stiffness and force are regulated by activation and active force production, thereby providing a simple explanation for many observations that remain unexplained with the 2-filament sarcomere model of the cross-bridge theory. These hitherto unexplained phenomena include the residual force enhancement, sarcomere and half-sarcomere stability, and the low energetic cost of eccentric contraction, which are readily explained with a 3-filament sarcomere model that includes titin as an activatable spring whose stiffness can be modulated by muscle activation and actin-myosin-based force production [ 33 ] Fig.
Proximal designated with cross signs and distal titin segment lengths dots in single sarcomeres of a myofibril stretched while it is in an activated state. Note that the proximal and distal titin segments initially elongate linearly with the elongation of the sarcomere, but after a short stretch, the proximal segment stops elongating while the distal segment accommodates the entire sarcomere stretch.
We interpret this result as an attachment of the proximal titin segment to actin after a short stretch distance, thereby only leaving the short and stiff distal segment to accommodate the sarcomere elongation. When myofibrils are stretched passively, the proximal and distal segments are stretched throughout the entire stretch phase in the same manner as indicated in this figure prior to titin attachment to actin, indicating that titin to actin binding does not take place in passively stretched muscles results not shown.
Stress vs. In the region beyond actin-myosin filament overlap beyond the grey shaded area , one would expect the force in the passively and actively stretched sarcomeres to be the same as cross-bridge based active forces are eliminated in this region. However, this was not the case and sarcomeres stretched beyond actin-myosin filament overlap had titin-based forces that were 3—4 times greater in actively compared to passively stretched myofibrils when stretching started at a sarcomere length of 2. When stretching started at average sarcomere length of 3.
When titin is eliminated from the myofibril preparation, all passive and active force production is eliminated as well, indicating that i titin is required for active force transmission, and ii that titin is the only force carrying structure in single sarcomeres once sarcomeres are stretched beyond actin-myosin filament overlap. Combined, these results suggest that titin produces more force in actively compared to passively stretched muscles. The mechanisms of how this titin-based increases in force are achieved remain unknown but are thought to occur through an increase in titin stiffness caused by calcium binding to titin upon activation as shown by Labeit and Duvall [ 29 , 30 ], and by titin binding to actin as shown in our laboratory [ 16 , 17 ].
Adapted from Herzog and Leonard [ 31 ], with permission. Upon muscle activation, titin is thought to bind calcium, thereby increasing its inherent spring stiffness, and also to bind its proximal segment to actin, thereby shortening its free spring length and thus further increasing its stiffness. The left and right top figures indicate two different initial sarcomere lengths. Stretching the sarcomere passively to a given length will lead to the same passive force centre and titin is stretched without attaching to actin.
Stretching the sarcomere actively to a given length left and right bottom figures will result in increased titin-based force because of calcium binding to titin and titin binding to actin, as explained in the text.
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Forces in the actively stretched sarcomere will depend on the initial length prior to the start of stretching, because titin is thought to attach at different points on actin, predicting that a longer stretch distance bottom left figure will result in a more increased force than a shorter stretch distance bottom right figure. In the active stretch, the passive force starts at a shorter sarcomere muscle length, and passive force is stiffer than for the passive stretch because of the engagement of titin with actin and because of calcium binding to titin upon muscle activation.
Note, how far the shift in passive force is, and how much stiffer the passive titin-based force is in actively compared to passively stretched muscle depends crucially on the initial sarcomere length and the amount of stretch. Adapted from Herzog [ 14 ], with permission. Titin binding to actin upon activation is thought to decrease the free spring length of titin and therefore make it stiffer [ 15 ].
A stiffer titin would then produce more force when a muscle is stretched actively compared to when the muscle is stretched passively. The same is true for titin stiffening upon activation. It has been shown that in active muscle, calcium binds to specific sites on titin e.
Therefore, the residual force enhancement can be explained by the engagement of titin upon activation as has been suggested based on early theoretical [ 35 , 37 ], and first ever experimental evidence of passive contributions to the force enhancement property of skeletal muscle [ 18 ]. In summary, there is good evidence that titin force is greater when a muscle is actively stretched compared to when it is passively stretched, and this additional force can explain at least part of the residual force enhancement property. Sarcomere and half-sarcomere stability can be explained by titin, because titin has been shown to centre the myosin filament [ 40 , 41 ].
In the absence of titin, neither passive nor active forces can be transmitted from one end of a sarcomere to the other end, sarcomeres and half-sarcomeres become unstable and no force can be produced [ 31 ]. Titin provides stability to the half-sarcomere by providing resistance when thick filaments are moved away from the centre of the sarcomere.
Similarly, when sarcomeres and single myofibrils are stretched in an activated preparation, force will continuously increase because of the increased stiffness in titin in active compared to passive muscle, thus providing positive stiffness at all lengths, including the descending limb of the force-length relationship and even when sarcomeres are pulled beyond actin-myosin filament overlap. This positive stiffness provides the stability to half- and full sarcomeres on the descending limb of the force-length relationship, as first shown by us when pulling single myofibrils onto the descending limb of the force-length relationship and observing perfect sarcomere length stability in the presence of great sarcomere length non-uniformities [ 23 ].
Finally, the reduced metabolic cost of eccentric contractions, and the reduced ATP consumption per unit of force for muscles in the force-enhanced compared to a purely isometric reference state [ 42 ] can also be explained with titin. According to the titin contraction theory [ 14 , 15 , 17 , 36 ], titin binds to actin upon muscle activation and stays bound even when the muscle is deactivated [ 18 ].
Replacing some of the eccentric force with a structural element, such as titin, thus reduces the metabolic cost of eccentric contractions and makes them energetically highly efficient. The fact that the cross-bridge theory on its own produces muscle force and sarcomere length instabilities [ 5 , 21 , 22 , 43 ], cannot account for residual force enhancement and other time-dependent properties of muscles [ 8 , 9 , 44 ], and is unable to predict the energetics and force changes in eccentric contractions properly [ 1 , 7 ] has been known for a long time.
However, powerful and unreserved support for the cross-bridge theory, and its beautiful predictive properties for steady-state isometric and concentric conditions, has resulted in a diminished attention to the shortcomings of this theory. Even to date, many scientists believe that sarcomeres are unstable on the descending limb of the force-length relationship and that residual force enhancement and other time-dependent properties can be accounted for by assuming that selected sarcomeres are rapidly pulled beyond actin-myosin filament overlap they are thought to pop , despite ample direct evidence to the contrary.
Therefore, the future challenges relating to the molecular mechanisms of muscle contraction may be summarized as follows:. Determine the role of non-actin myosin-based force regulation. Titin is thought by some to bind to actin, thereby shortening its spring stiffness and force upon muscle sarcomere stretching. Determine if this is indeed correct, and identify the possible binding sites between titin and actin and what forces these binding sites can withstand. In conjunction with this work, and if titin indeed binds to actin, then it becomes likely that Ig domain unfolding will occur at physiologically relevant muscle length.
The kinetics of Ig domain unfolding and refolding will then become a crucial aspect of force production in muscle and needs to be determined in great detail. Identify if there are structural proteins other than titin that might be involved in muscle force regulation. Identify if sarcomeres are indeed the smallest independent contractile units in muscle.
Evidence suggests that serially arranged sarcomeres in a myofibril are not independent of each other. Rather it appears that force along sarcomeres is collectively controlled, either by mechanical connections between sarcomeres or by feedback systems that regulate cross-bridge kinetics. The former solution is more appealing as it merely requires cross-connections across the Z-band, while the latter would require a sensing and information exchange mechanism between serially arranged sarcomeres in a myofibril.
Similar to our restricted understanding of how muscles contract on the molecular level, there is much to learn about in vivo muscle function. The basic properties associated with muscle force production are the force-length relationship [ 5 ], the force-velocity relationship [ 6 ] and the history or time -dependent properties of residual force enhancement and force depression [ 44 ].
Even though these properties represent the basis for all muscle function, we know virtually nothing about them for in vivo muscle contraction. For example, I could ask the question, what is the force-length, force-velocity, and history-dependent property of the human rectus femoris muscle, and nobody would be able to give a satisfactory answer. Typically, for human muscle function, researchers rely on the moment-angle relationship of a muscle, rather than the force-length relationship.
This representation has many advantages. For example, human joint moments can be readily measured using specialized and commercially available dynamometers, and joint angles can be determined with great accuracy while muscle lengths cannot. Nevertheless, moment-angle relationships typically represent the moments produced by a synergistic group of muscles, and often are thought to contain antagonistic contributions.
Therefore, if we want to know the contribution of a single muscle to the resultant joint moment, basic and non-trivial assumptions need to be made. Such an approach contains many non-trivial assumptions, among them the following:. Many of these assumptions are known to not be correct for at least some muscles that have been studied.
For example, it has been shown that the joint angle of maximum moment does not necessarily coincide with the angle at which the maximum moment arm occurs [ 47 ], so, the force-length relationships of synergistic muscles are not necessarily the same [ 48 ], and submaximal activation of muscles changes fascicle optimal lengths in a complex and often unpredictable manner [ 49 ].
Finally, the optimal lengths of 2-joint muscles in a synergistic group for example the rectus femoris in the knee extensor muscles depend on two joint angles hip and knee for the rectus femoris , thus contributions to moments at one joint the knee will depend on the configuration of the other joint hip. Therefore, the assumption of a constant contribution of a muscle to the moment-angle relationship throughout the entire range of joint motion and at all speeds of contraction, is likely not correct. Needless to say, the situation becomes infinitely more complex if we want to study muscle function during everyday movements.
In such situations, not only the force-length, but also the force-velocity and history-dependent properties start playing an important role, and the muscle force is variable and transient and not at steady-state, conditions that have not been described well for single human skeletal muscles. Maybe most importantly, everyday movements are typically performed using sub-maximal levels of muscle activation. Often it is assumed that the basic muscle properties can be scaled linearly from maximal to submaximal levels of activation.
However, it has been known for a long time that submaximal force-length relationships are not merely linearly scaled versions of the maximal relationship e. Maximal and sub-maximal force length relationship for human vastus lateralis muscle. The fascicle lengths were directly determined using ultrasound imaging while the forces were obtained making the usual assumptions discussed above. Note how the maximal and sub-maximal relationships do not scale linearly, and how optimal fascicle length, but not optimal muscle length, is about constant in this approach where the relationship was derived for sub-maximal levels of activation rather than sub-maximal levels of force.
The numbers on top of the graph ranging from to 80 indicate the corresponding knee joint angles.
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Adapted from [ 49 ], with permission. I assume that it will not be possible to measure the mechanical properties of the individual muscles comprising an agonistic group of human skeletal muscles and their respective force-time histories during everyday movements in the near future. However, theoretically at least, such measurements are relatively straight forward in an agonistic group of muscles in an animal preparation. For example, the maximal force-length relationships of the individual cat ankle extensor muscles have been determined [ 48 ], and the corresponding force-time histories have been determined for a variety of everyday tasks ranging from standing to walking, running, galloping, jumping, scratching and paw-shaking [ 52 — 58 ].
Determining the corresponding history-dependent properties, and force-velocity properties has been done partially, but submaximal relationships for these mechanical properties have not been, but could be easily determined. Although it is fairly trivial to determine the mechanical properties of isolated muscle preparations, fibres or myofibrils, it remains a great challenge to determine the basic muscle properties for individual in vivo human skeletal muscles using voluntary and thus inconsistent contractions.
The following challenges should be tackled in the next two decades:. It has been known for a long time that muscles deform during contraction. Hundreds of years ago, muscle contraction was thought to occur through the invasion of spirits that deform muscles and this deformation was thought to cause longitudinal contraction and force production. The classic study by Griffith [ 59 ], who performed first fibre length measurements in a muscle of a freely moving cat, demonstrated that fibre and muscle tendon unit length changes can be in opposite directions.
Griffiths [ 59 ] showed that muscle fibres shortened in the cat medial gastrocnemius at the beginning of the stance phase of walking while the muscle tendon unit was substantially stretched at that same instant in time. Since in this phase of cat walking, force is increasing, the shortening of the fascicles was associated with a corresponding stretch of the series elastic elements.
Again, this shortening was associated with the increase in force in isometric contractions and the corresponding stretching of serially arranged visco- elastic elements. So, what is series elasticity? In a special issue of the Journal of Applied Biomechanics that was focused on the storage and release of elastic energy in skeletal muscles, the late Gerrit Jan van Ingen Schenau defined series elasticity as follows [ 61 ]:. This definition has been largely accepted and used in a variety of studies in prominent journals.
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However, if this definition is used to make statements about the mechanics of muscles, for example to calculate the storage and release of elastic energy, then one must be careful and adhere strictly to the laws of mechanics, otherwise erroneous results may be produced and the interpretation of storage and release of elastic energy may take forms that are thermodynamically impossible.
For example, muscle forces are typically measured using tendon force transducers, and there is no doubt that the external tendons of muscles are in series with the muscle itself, that is, the tendon transfers the force that is produced by the muscle and the tendon force represents the muscle force. However, if we now take a muscle, for example the medial gastrocnemius of a cat Fig. However, it is easy to show that aponeuroses do not transfer the same amount of force as the tendon or the muscle, and that aponeuroses forces vary along their lengths [ 62 ]. Scaled representation of a mid-longitudinal section of a cat medial gastrocnemius muscles obtained through chemical fixation.
Note the pennate architecture of the muscle, the long free tendon, and the long medial and lateral aponeuroses. For a typical stretch shortening cycle, starting from zero force and returning to zero force, we know that an elastic element cannot produce any net energy. However, all biological tissues, such as tendons and aponeuroses are at least slightly visco-elastic, thus there is a small loss of energy for all stretch-shortening cycles. Not only that, but Fig. However, a series elastic element must elongate with increasing force and must shorten with decreasing force.
Such a behavior is not observed in aponeuroses in general [ 45 , 63 , 64 ]. Force in the cat medial gastrocnemius as a function of changes in tendon and aponeuroses lengths obtained by subtracting fibre lengths from the total muscle tendon unit lengths. Note that plotting the muscle force against this length defined incorrectly as the series elastic element of the muscle -[ 61 ] results in the appearance of net work by the incorrectly defined series elastic element, a thermodynamic impossibility.
This example illustrates that the nature of the series elastic element is difficult to define, and is often used incorrectly leading to conclusions on the storage and release of energy in muscle contraction by series elastic elements such as aponeuroses that are incorrect. Directly measured cat medial gastrocnemius force as a function of the directly measured length of the corresponding lateral aponeuroses.
Forces were measured using a standard buckle type force transducer [ 48 , 52 — 59 ] and aponeurosis lengths were measured using two sonomicrometry crystals aligned along the mid-longitudinal collagen fascicles of the aponeurosis [ 83 ]. These direct force and elongation measurements indicate that there is no relationship between force and the elongation of the lateral aponeuroses, therefore the aponeuroses length is NOT an indicator of muscle force and is not in series with the muscle force tendon.
The solution to the problem of series elasticity is as simple as it is relevant; only use the term series elasticity in the calculation of storage and release of mechanical energy in the mechanically correct way. In most maybe all situations, this will lead to incorrect results, typically an overestimation of the contribution of series elastic elements to the storage and release of elastic energy in stretch-shortening cycles.
Furthermore, aponeuroses are complex 3-dimensional structures that deform based on the internal stresses of the muscles and these include pressure and shear stresses that are often not accounted for properly in muscle models [ 65 , 66 ]. Also, aponeuroses do not only experience longitudinal strains but are exposed to multi-dimensional strains that may affect the longitudinal strain behavior [ 67 , 68 ] and must be considered for proper understanding of aponeuroses mechanics. Finally, aponeuroses transmit variable forces along their lengths and widths [ 62 ], and these cannot be measured presently, and thus we must rely on theoretical models to predict the variable stresses in these tissues.
I would love to see the following problems in whole muscle mechanics and in vivo muscle function solved:. Simply formulated, the distribution problem deals with the idea of how joint moments and thus joint movements are accomplished by the different force carrying structures crossing a joint. The resultant joint moments, typically, can be determined easily using the so-called inverse dynamics approach [ 69 ]. For example, in order to calculate the resultant joint moments in the human lower limb during locomotion, all one needs is a force platform that measures the external ground reaction forces acting on the foot during locomotion, the three-dimensional movement of the lower limb, and the inertial characteristics mass, moment of inertia, and centre of mass location of the lower limb segments [ 69 ].
Once the resultant joint moments have been calculated as a function of time, it is obvious that this resultant joint moment is equipollent to the moments by all individual force carrying structures that cross the joint of interest. Structures that can contribute to the resultant joint moment are the muscles, ligaments and bony contact forces. Other structures crossing the joint blood vessels, nerves, joint capsule, etc. Mathematically, the distribution problem is then expressed as:. Equation 1 is captured pictorially in Fig.
The dystroglycan complex, which forms a crucial structural and functional link between the intracellular cytoskeleton actin and the extracellular matrix. For a single muscle fibre the force of contraction is proportional to the number of actin—myosin bonds formed. This will be optimal when the initial sarcomere length is such that all myosin heads are overlapped by thin filaments. If the sarcomere is stretched too far, the central myosin heads will be redundant. If the sarcomere is too short, the distance between the actin and myosin binding sites increases and their alignment may also be distorted, both of which will reduce the efficiency of contraction.
However, unlike in cardiac muscle, skeletal muscle fibres are maintained near their optimal length in their working range; therefore, the Frank-Starling length—tension relationship is not a major factor in skeletal muscle physiology. Consequently, the force generated by a single skeletal muscle fibre will be a function of both the cross-sectional area and the length of the fibre. The same relationship applies to the muscle as a whole. Of course, it would not be very useful if each muscle could contract only at its maximum force.
Graded muscular contraction is achieved through two main mechanisms: summation and recruitment. If a second stimulus is applied to the muscle before it has fully relaxed from the first, the response to the second stimulus will add to the residual response of the first stimulus. Between stimulus frequencies of 20—50 Hz the summed responses form a smooth ramped increase in tension, or tetanic response.
The usual firing frequency of vertebrate motor neurons is within the tetanic range.
Single motor neurons innervate multiple muscle fibres. A motor neuron and the muscle fibres it innervates are collectively called a motor unit. The number of muscle fibres within a motor unit varies within and between muscles. The smallest motor units, containing as few as 3—10 muscle fibres, are found in muscles used for fine intricate movements. Much larger motor units, containing up to several hundred muscle fibres, are predominant in muscles used for gross vigorous movements.
When a muscle is required to produce a progressive increase in tension, initially, when the load applied to the muscle is small, the smallest motor units within the muscle are used. As the load increases larger and larger motor units are recruited, so that when the load is the maximum attainable by that muscle, all its motor units will be operating. We have seen that ATP is required for significant tension to develop and it is also crucial for muscle relaxation. Muscle has a specialized means of storing high-energy phosphate in the form of creatine phosphate.
ATP is derived from creatine phosphate by the action of creatine kinase but the so-derived ATP is sufficient to maintain contraction for only a further 5—8 s. More prolonged contractile activity requires synthesis of ATP by intermediary metabolism. Aerobic metabolism of 1 mole of glucose produces 38 moles of ATP but even maximal oxygen delivery is insufficient to meet the demands of vigorous muscle activity. Anaerobic metabolism is less efficient in that 1 mole of glucose produces only 2 moles of ATP, but the ATP produced is more readily available. However, this is at the expense of a build-up of lactate, which is an important factor in the development of muscle fatigue.
Most human muscles contain a mixture of fibres within this range. The thinner fibres are type I fibres and they are adapted for sustained activity requiring submaximal tension generation. The thickest fibres type IIb are adapted for short bursts of near-maximal activity. Muscles containing a predominance of type I fibres appear a deeper red colour than those with few type I fibres because type I fibres have a high myoglobin content.
Myoglobin is pigmented because of a haem moiety that is responsible for its oxygen-binding capability. Myoglobin provides a storage capacity for oxygen within muscle cells; its affinity for oxygen is greater than that of haemoglobin, which aids oxygen delivery to muscle, but is such that oxygen is released for aerobic metabolism when demand is increased. Type IIa fibres are intermediate in size and myoglobin content. Other physical and metabolic characteristics of the different fibre types are described in Table 2.
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Volume 6. This article was originally published in. Article Contents. Electrical events in muscle contraction.
Excitation-contraction coupling. Contractile structures. Determinants of force of contraction. Energy for contraction. Muscle fibre-types. Innervation of alpha motor neurons from the central nervous system has a large part in determining the fiber type that is expressed within muscles. Co-expression of fiber types within a single muscle fiber has been seen in motor neuron diseases such as Amyotrophic Lateral Sclerosis ALS and Spinal Muscular Atrophy [ 33 ].
In these diseases, specifically ALS, studying disease influence on skeletal muscles would provide valuable insight to the mechanisms of disease progression. Changes in muscle fiber types may occur at the early stage of diseases by reduced inputs from motor neurons, as disconnections between muscle and axon terminals have been observed in animal models of motor neuron diseases before symptom onset. Switches in muscle fiber type has been observed in patients in motor neuron diseases, however the switches cannot prevent the ultimate outcome: apoptosis and necrosis of individual muscle fibers [ 27 ].
Often, motor neuron diseases are diagnosed clinically via histochemical staining of muscle biopsies. Necrosis can be easily seen as fat or scar tissue under the microscope, but apoptosis is harder to identify due to the lack of inflammatory response from the body [ 27 ]. Denervation of the muscle results in upregulation of pro-apoptotic genes, such as bax and anti bcl-2, which are upregulated due to intrinsic cell stress.
This includes destruction of the nuclear lamina, the nuclear envelope, and DNA destruction [ 27 ]. Motor neuron degeneration and neuromuscular junction denervation rapidly result in decreased motor function. Although a disease cause of sporadic ALS has not been specified, this disease is generally regarded as resulting from factors involving environment, lifestyle, aging, and genetic predisposition [ 36 ]. Several proposed pathological mechanisms of disease include protein misfolding and aggregation, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, glial cell activation and related inflammatory processes, and axonal transport defects [ 37 ].
ALS causes motor neuron death and gradual denervation of skeletal muscles over time. This denervation causes loss of muscle function and muscular atrophy within affected cells, ultimately resulting in cellular death due to apoptosis. This hypothesis states that irregularities within the skeletal muscle are the primary cause of ALS, denervating muscle and motor neuron [ 39 ]. Based on this hypothesis, possible contributions of skeletal muscles and neuromuscular junctions in ALS pathology have been proposed in recent studies. Specifically, our research group also reported that using stem cells to deliver growth factors directly into the skeletal muscle could restore motor function in a rat model of familial ALS [ 40 , 41 , 42 ].
This section controls muscles in the face, neck and head. Bulbar onset usually affects voice and swallowing first. Patients with bulbar onset have a correlation between the age of death and the loss of slow tonic fibers, although there is neither correlation seen in spinal onset ALS nor controls [ 34 ]. ALS pathology affects skeletal muscle in many ways, which seems to influence muscle fiber type changes.
Autopsies show fiber atrophy, fiber grouping, fiber splitting, with increased fatty tissue and connective tissue [ 43 ]. Interestingly, unlike atrophy from exercise, ALS shows a fast to slow fiber type switch [ 39 , 44 ]. In the hindlimb muscle tibialis anterior muscle of pre-symptomatic ALS model mice, there is denervation of the most forceful and fast to fatigue fibers Type IIB only found in mice.
This results in transitions to fast motor units with intermediate fatigue and fatigue resistant fibers. Although this transition is present, it is not a sudden change nor a complete loss of Type IIB fibers [ 44 ]. Biopsies taken from atrophied skeletal muscles in patients with ALS have shown that individual muscle fibers contain myosin isoforms corresponding to both fiber Types I and II, termed a mixed fiber type.
An early pattern of denervation can be detected and has the potential to be used for diagnostic purposes. This pattern is individual fibers with a mixed fiber type and little fiber type grouping, all within an atrophying muscle [ 45 ]. It has been reported that specific muscle groups such as extraocular muscles are relatively spared from the disease phenotype in ALS [ 46 ]. Motility of the eye is often maintained in ALS patients [ 47 ] and autopsies have shown the extraocular muscles do have some muscle fiber pathology compared to control, but in relation to other ALS affected skeletal muscles in the body, the extraocular muscles were well preserved [ 43 ].
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The pathology that was seen include change in fiber type composition, the cellular architecture, and decreased overall MyHC content. This preservation of extraocular skeletal muscle is accredited to the distinct fiber type composition within the extraocular muscles. Extraocular muscles have a unique myosin expression that is not found in skeletal muscles located other places of the body. Although there is great speculation, the exact mechanism of why extraocular muscles are spared in ALS is unknown.
However, one interesting hypothesis is the multiple innervations of slow tonic fibers serve as a protective mechanism against the neurodegenerative disease [ 48 ]. It has also been found that the motor neurons of the extraocular muscles have different surface markers than motor neurons found elsewhere in the body, suggesting they have properties that make the neurons less susceptible to disease [ 49 ]. As an additional note, similar specific insusceptibility in the extraocular muscles has also been observed in Duchenne Muscular Dystrophy [ 50 ].
Another question is how sex influences fiber type specification in the muscle during ALS pathology. The exact etiology of ALS is still uncertain, but most epidemiological studies have shown a higher incidence of ALS in men than women. Interestingly, sexual dimorphism in disease onset and progression is also observed in rodent models of familial ALS [ 51 , 52 ]. Although it is still uncertain whether such sexual differences are originated from the intrinsic difference in individual cells [ 53 ], further studies would be required to answer this question. Spinal Muscular Atrophy SMA is a group of motor neuron diseases, which are autosomal recessive in nature.
Each SMA type has a different clinical outcome, however all SMA types commonly demonstrate motor neuron degeneration caused by insufficient expression of a specific protein named Survival of motor neuron SMN [ 54 ]. I is infantile SMA that causes death early in childhood and IV involves some motor neuron loss, but allows for a normal life expectancy [ 55 ].
The SMA disease is present in a spectrum of disease severities ranging from infant mortality, in the most severe cases, to minor motor impairment, in the mildest cases. The variability of disease severity inversely correlates with the copy number, and thus expression of a second, partially functional survival motor neuron gene, SMN2.
This meaning that there were more Type I fibers in the soleus muscle and Type II fibers in fast twitch muscles transitioned to a more oxidative fiber type [ 54 ]. These same mice also had smaller motor neurons units than controls and the Type I motor neurons decreased in size as the disease progressed.
Other studies that have used type III SMA-induced mice have shown to have increased fiber type grouping compared to wild type [ 56 ]. There has been evidence that these pathological changes in muscle fiber types can be reversed. Swimming aided the mice to regain more glycolytic fast twitch fibers, and restore Type I motor unit size close to wild type levels [ 54 ].
Upon completion of exercise intervention by type III SMA-induced mice, their structure and number of the Type I fibers were comparable to controls [ 54 ]. In humans, it has been shown that innervation of fibers in children with SMA specifically Werdnig-Hoffmann disease is incomplete.
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This further emphasizes the need for motor neuron innervation for Type II fibers to prevail [ 4 , 57 ]. Muscle fiber type composition is primarily determined during development but will be altered by physiological and pathological conditions. Significant changes of fiber type composition have been identified in the muscles with a background of major neuromuscular diseases. To further understand the roles of muscle fiber composition in skeletal muscle development and diseases, additional studies using new research approaches may help us understand how muscle fiber type specification occurs during development and disease conditions.
For instance, skeletal muscle cell culture derived from human pluripotent cell resources can provide a new tool to study how human skeletal myocytes differentiate into myotubes with specific fiber types in culture [ 58 , 59 ]. These studies could highlight what specific mechanisms are involved in the significant changes of fiber type composition and ratio in the skeletal muscle during embryonic myogenesis and under disease conditions, and how these changes of muscle fiber types impact on muscle physiology and pathology.
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Downloaded: Abstract In the human body, there are individual skeletal muscles that allow us to perform a variety of functions such as executing locomotive tasks, breathing, and moving our eyes. Introduction Skeletal muscle is the most abundant tissue in human body.