physiology (two pages)

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MUSCLE PHYSIOLOGY

Part 3: Muscle Mechanics Learning Objectives:

1. Compare and contrast isometric and isotonic contraction and what type of information can be obtained from each type of measurement.

2. Construct a length‐tension curve, including active, passive, and total forces and relate it to muscle structure.

3. Construct a force‐velocity curve and list the factors that govern its shape in skeletal muscle.

4. Describe the determinants of pre‐load and after‐load and how pre‐load affects after‐load. 5. Describe how ATP levels are maintained in muscle cells. 6. Describe the classification of muscle fiber types 7.

A. OVERVIEW

The primary function of muscle is mechanical: to develop force and to perform work. Secondarily, muscle produces heat, a function vital to the maintenance of body temperature. The following section applies to all muscle types, skeletal, cardiac, and smooth. Muscular activity can be divided into two categories, force generation and muscle shortening. Force generation can be measured as an isometric contraction and muscle shortening can be measured as an isotonic contraction.

Isotonic Contraction. If the ends of a muscle are free to move when activated, filaments will slide and the muscle will shorten. In mechanical experiments involving iso (constant) tonic (force) contractions, the muscle is fixed at one end, usually to a force transducer, while the other end can move (Figure 1A). Changes in length are measured either directly or by the movement of a length transducer to which the free end of the muscle is attached. Upon stimulation, the muscle will first develop force isometrically to a level that is equivalent to the weight of any load on the muscle and then it will shorten isotonically ‐ more on this later. During shortening, the force produced by the muscle, that is required to lift the load, is constant. Because of the arrangement of muscles in vivo, almost all motion is based on a combination of isometric and isotonic contractions.

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B. ISOMETRIC CONTRACTIONS If the ends of a muscle are held fixed and it is activated, the muscle will not be able to shorten (Figure 1B). The cross‐bridges will cyclically attach to actin, pull, generate force, detach, with minimal filament sliding. It is minimal and not zero as some sliding will take place to take up the elasticity in the muscle. We can measure the force produced by the muscle. Experimentally, the ends of the muscle are immobilized with one end attached to a force transducer and the other to a micrometer so that the length of the muscle can be set prior to stimulation. Upon stimulation, the muscle develops force without a change in overall length ‐ iso = constant, metric = length. Force is usually expressed in terms of cross‐sectional area of the muscle and therefore muscles with larger cross‐sectional areas generate higher forces.

  Figure 1

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Isometric length‐force relation Length‐force relation of the sarcomere ‐ the length of a sarcomere prior to stimulation is a fundamental determinant of the amount of force that the sarcomere can develop. The active force is directly proportional to the number of sites of mechanical interactions through the crossbridges, between the thick and thin filaments. This is determined by the degree of overlap of the two filaments within the contractile lattice. Length‐force relation in whole muscle ‐ It is not possible to determine directly how active force varies with muscle length because of the presence of non‐ contractile or passive elements that resist stretch or force when the resting muscle is stretched beyond a critical length. These passive elements include connective tissue sheaths that surround muscle bundles, the sarcolemma itself, and entities such as titin filaments within the individual sarcomeres. To quantify active force produced as a function of muscle length, it is necessary in a whole muscle to determine the contributions of force derived from passive elements to the total force that is measured. This is accomplished by measuring the passive force produced when a resting muscle is stretched to a given length and then the total force at that length. The arithmetic difference in these two forces will equal the active force. Passive elements and muscle length Resting muscle is an imperfect elastic body ‐ it resists stretch by exerting passive or resting force. The relationship between the length of a resting muscle and the force it exerts in resisting a stretch is non‐linear. When a resting muscle is stretched, connective tissue elements are extended. The elements are initially compliant then they sharply resist further extension as they are stretched. It is important to note that the contractile elements offer no resistance because no crossbridges are attached in resting tissue and the filaments are free to slide. The shape of the passive force‐length curve depends on the type and amount of connective tissue (Figure 2). Elastin for example is very compliant as compared to collagen. The elastin component contributes mainly to the ʺfootʺ of the passive force‐length curve while the sharp rising portion reflects the collagen component. As the amount of connective tissue in a muscle increases relative to the amount of muscle tissue, the passive force curve shifts to the left (relative to the length axis). This occurs in cardiac and smooth muscle.

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  Figure 2

Total force and muscle length At any length, the total force output of an activated muscle is the sum of the passive force and the active force produced by crossbridge interactions following stimulation. The relative contribution of passive and active elements to total force can be distinguished through determination of the length‐force relationships of the muscle.

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How to determine the isometric length‐force relationships

  Figure 3

A resting muscle is stretched, in a step‐wise fashion; at each step, length is held constant and the muscle is maximally stimulated isometrically (Figure 3). At each length, the resting or passive force is recorded prior to stimulation. At each length, passive force prior to stimulation is subtracted from the total force developed upon stimulation ‐ this provides active force. Note that at short muscle lengths, all of the total force is active whereas at longer muscle lengths, the contribution of passive force to total force increases sharply. At these longer lengths, even though the total force is high, the active force may actually be quite low. The low active force is due to decreasing filament overlap; the high passive force is due to connective tissue elements.

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Active force and muscle length Active force is the force produced or developed by the contractile elements (myosin and actin proteins) upon stimulation. The active force curve obtained for a tetanically stimulated skeletal muscle describes the maximum force that the muscle can develop at each muscle length. In a whole muscle, as in the single fiber or sarcomere, there is an optimum length for active force production called Lo or Lmax (Figure 4). Active force curve also shows the minimum and maximum lengths at which force can be developed. A typical range for skeletal muscle is as short as 65% and as long as 135% of the optimal length.

  Figure 4

C. ISOTONIC CONTRACTIONS Method of measuring Under isotonic conditions, a muscle is able to shorten upon stimulation. While the force on a muscle prior to stimulation based on length is the pre‐load, the load or resistance which the muscle must contract AGAINST is the after‐ load. These two terms are critically important, especially for a complete understanding of cardiovascular function. The sequence of events that occur during a typical contractile event (such as picking up a cup of coffee, Figure 5) are: 1) an increase in isometric force to overcome the weight of the load (the weight of the cup); 2) isotonic shortening or contraction as the

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weight is lifted (lifting the cup to your mouth); 3) isotonic relaxation as the weight is returned to the table (lowering the cup to the table); 4) isometric relaxation as the muscle relaxes since no load is present (letting go of the cup).

  Figure 5

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  Figure 6

Note that if the load is small, only a small amount of isometric force needs to be developed; if the load is large, a large isometric force needs to be developed. With increasing loads, the delay to shortening is increased as the muscle needs more time to develop more isometric force. As afterload increases the rate of isotonic shortening decreases. Remember pre‐load is ONLY the force (length) on the muscle PRIOR to stimulation and NOT the weight that the stimulated muscle is lifting or working against; this latter weight determines the AMOUNT of isometric force that must be developed before shortening can occur. In a normal physiological situation, skeletal muscle is almost always at a pre‐ load that sets the muscle at near Lo, the length for optimal force generation. However, as you will learn in the Cardiovascular Module, pre‐load in cardiac muscle can change on a beat‐to‐beat basis and therefore change the position

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of the muscle along itsʹ length‐force relationship. We will also see this in the smooth muscle lecture that pre‐load can change.

  Figure 7

Isotonic Contraction and the Length‐Tension Relationship The way in which length (pre‐load) determines the magnitude of active force that can be developed by a muscle is defined by the isometric length‐active force relationship. This relationship also defines, in part, the rate of shortening that a muscle can undergo during isometric force conditions. This is because before a muscle can undergo isotonic shortening, it must first develop the isometric force to match the load, and based on the length/tension relationship ��length determines the amount of force that can be maximally developed. But remember the whole muscle does NOT have to develop

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maximal force; it can develop any increment of force from zero UP TO the maximum.

Force‐Velocity Relationship

  Figure 8

During an isotonic contraction, the muscle shortens under a constant load. The dependence of the rate of shortening on the magnitude of the load is known as the Force‐Velocity Relationship. Shortening or velocity of shortening of a whole muscle is the ʺorganʺ level equivalent of actin‐activated myosin ATPase activity. Figure 6 and 7 shows the effect of clamping a single twitch contraction at increasing afterloads (increasing force against which the muscle must shorten). Note that as the afterload increases the velocity of shortening decreases.

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Figure 8 shows the full force‐velocity relationship for a skeletal muscle. Note that at zero velocity, maximal isometric force is generated. At maximal velocity, no load is generated.

  Figure 9

Figure 9 shows the relationship between the Length/Tension and Force/Velocity curves. At Lo (length at optimal thick and thin filament overlap and therefore absolute maximal force development for that muscle), one discrete force/velocity curve can be obtained. At lengths shorter and longer than Lo (and therefore at different pre‐loads), the active force that CAN be developed is less and therefore the X‐intercept on the force axis of the Force/Velocity curve is shifted to the left, that is, to lower maximal forces.

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Note that maximal velocity (Y‐intercept) is not changed. The maximal velocity of shortening is determined (in striated muscle) only by the isoform of myosin present in the muscle. Slower isoforms of myosin will decrease maximal velocity of shortening resulting in a downward shift on the Y‐ intercept whereas faster isoforms of myosin will result in an upward shift on the Y‐intercept. All other points on the Force/Velocity curve are velocities; there is only one MAXIMAL velocity and that occurs at zero load.