Skeletal Muscle Aspects of Fatigue - YR1 Lecture 1H 2022

SKELETAL MUSCLE ASPECTS OF FATIGUE Professor Stewart Head Email: [email protected] 1 1 Learning objectives Describe the cellular process responsible for producing fatigue in the following activities: 100m sprint; sustained contraction (like holding a Piano over your head); five kilometre r...

SKELETAL MUSCLE ASPECTS OF FATIGUE Professor Stewart Head Email: [email protected] 1 1 Learning objectives Describe the cellular process responsible for producing fatigue in the following activities: 100m sprint; sustained contraction (like holding a Piano over your head); five kilometre race, and running a marathon. Identify the intra-muscular sites where fatigue occurs. Muscle fatigue: describe the clinical implications for humans. 2 2 1 Overview Skeletal muscle fatigue is usually defined as the reversible decline of performance during activity, and most recovery occurs within the first hour 3 3 Muscle fatigue An elite athlete can run 100m in 10s, naively you might assume the same athlete could run 1000m in 10X10s=100s, but in fact the world record is around 135 seconds. Similarly for 10000m the world record is not 1000s but 1600s. The human machine is different to say a car which will maintain maximum speed until the fuel runs out and then stop. 4 4 2 REPRESENTATIVE SHORT ANSWER QUESTION Compare and contrast the mechanisms responsible for skeletal muscle fatigue in the following activities: (i) A 100m sprint.(3 marks) (ii) A sustained contraction (like holding a Piano over your head). (3 marks) I will refer to this as we go through the lecture to give you an idea of the type of answer required. 5 5 Techniques used by scientists to study fatigue 6 6 3 Where does this decline in performance “fatigue” originate? The main site is in the muscle, the CNS and peripheral nerves make a smaller contribution. (Merton 1954, Classic experiment) doi: 10.1113/jphysiol.1954.sp00 5070 Fig legend. Apparatus for recording simultaneous mechanical and electrical responses from the adductor pollicis. 7 7 The mechanism responsible for the drop in force from skeletal muscle during fatigue are due to: i) The build up of metabolic bi-products due to high rates of ATP utilisation inhibit contraction. ii) The major end cause of the force loss is that Ca2+ release from the Sarcoplasmic Reticulum progressively falls. (Look at your skeletal muscle lecture. “Ca2+ release from the SR triggers skeletal muscle contraction”) 8 8 4 Where is the site of fatigue in muscle? Note. The figure shows one sarcomere from a single muscle fiber. The t-tubules invaginate into the fiber (cell) twice a sarcomere at the A/I junction (revise the bands in straited muscle). The ttubules are closely aligned with the intracellular Ca2+ store, the sarcoplasmic reticulum. The molecule motor is shown in the bottom panel. The figure has been taken from (slightly modified) R. H. FITTS (1994). Cellular Mechanisms of Muscle Fatigue. PHYSIOLOGICAL REVIEWS Vol. ‘74, No. 1, 9 9 Lactic acid accumulation (acidosis?) The Lactic acid theory of muscle fatigue has lost the support of the mainstream scientific community. This fact is not yet reflected in many text book accounts. (See Video) 10 10 5 ATP; produces some metabolic bi-products which produce fatigue Free ATP enough to power contraction 2-3s If ATP runs out:-rigor (mortis) this would be an evolutionary pressure on the development of fatigue as a singling mechanism for low ATP Muscle has several back up sources of ATP production. Creatine phosphate directly recharges ATP, this supply lasts 2030s. 11 11 ATP sources during repetitive contractions Glycogen can be broken down anaerobically, this supply lasts for 2-3 minutes Glycogen can be broken down aerobically in the mitochondria, this supply of ATP is slower than the others but can keep the muscle contracting 30-60 minutes Once the glycogen is gone the muscle must rely on aerobic fat metabolism, slow but the stores are large 12 12 6 The 100 m sprint The running speed during a 100 m sprint is much higher than during longer runs; the short duration means that fatigue is less of a problem. However, even during short sprints there is some fatigue and the maximum running speed in a 100 m sprint occurs after about 60 m. Why does the running speed decline during such a short sprint? The answer to this is not entirely clear. It is, however, clear that lactic acid has little to do with it. Relatively little lactic acid is formed during such a short activity. Instead most of the energy comes from breakdown of phosphocreatine. Breakdown of phosphocreatine consumes hydrogen ions so the net effect is that myoplasmic pH is not significantly altered during the sprint. One product of phosphocreatine breakdown is phosphate ions and these have been shown to depress muscle function: they reduce both Ca2+-sensitivity of the contractile proteins (point 6 ) and the ability of the contractile proteins to produce force (point 7). Thus phosphate ion accumulation is probably an important contributor to fatigue during a 100 m sprint. 13 13 Continuous maximal contraction A continuous maximal contraction is needed when lifting something very heavy, like a piano. Everyone will be aware of how rapidly fatigue can set in during such activities. In this situation the muscle machinery is going at full speed and energy is consumed at a rapid rate. In addition, the blood flow to the active muscle(s) is stopped during maximal contractions so that no delivery of oxygen (to support muscle contraction) or removal of metabolites or ions will occur. Thus severe fatigue develops within seconds and the muscle becomes rapidly weaker. Each action potential is associated with entry of sodium ions into the cell and exit of potassium ions from the cell; consequently potassium ions tend to accumulate outside of the fibres and this results in depolarization and impaired electrical activation of muscle cells. This extracellular accumulation of potassium is likely to be larger in the narrow lumen of the t-tubules Points 1,2 14 14 7 The 5 km race Events of this sort last 10 or so minutes and are performed at quite close to the maximum capacity of the muscles and involve both the aerobic and the anaerobic ATP pathways. In isolated muscle fibres stimulated until fatigue there is a prominent failure of Ca2+ release from the SR (see Fig). It is easy to show that this decline of Ca2+ release is important in the failing muscle performance because caffeine can increase SR Ca2+ release and overcome (temporarily) much of the decline of force. Point 4 15 15 Running longer distances } marathon runners will be aware of the overwhelming muscle weakness experienced in the final stages of the race. This type of fatigue develops quite suddenly, known as ‘hitting the wall’, and correlates with the near final depletion of glycogen in muscles. Sian Welch & Wendy Ingraham - The Crawl - 1997 Muscle biopsies show that at the end of a marathon glycogen is depleted but ATP is only marginally reduced Lactic acid accumulation is minimal phosphate accumulation is also only moderate 16 16 8 Running longer distances Instead the main factor seems to be failure of calcium release inside the cells which is associated with the glycogen depletion. Phosphate entering the SR causes a ppt of Calcium phosphate to form causing a failure of calcium release. Point 4 17 17 Summary of muscle fatigue 18 18 9 Numerous disorders like cancer cachexia, general flammatory diseases, sepsis, burns, human immunodeficiency syndrome, chronic kidney failure, muscular dystrophy, as well as normal ageing are associated with a loss of skeletal muscle tissue. The decrease muscle mass result in decreased capacity to generate force; early fatigue development then occurs because muscles always have to work at a higher fraction of their maximal capacity. Note the actual fatigue resistance of the muscle cells may not be affected. Patients with congestive heart failure also show a decrease fatigue resistance which has intrinsic to defects in skeletal muscles. This is due to defects in both contractile proteins and SR calcium handling. 19 19 In the clinical setting, a careful analysis of the muscle function is important for designing optimal strategies to treat patients with decrease fatigue resistant. As described in the previous slide increased fatigue ability is frequently due to a general decrease in muscle force production rather than a decreased fatigue resistance of muscle cells. This means that a strength training program to increase, or avoid further loss of, muscle mass may improve fatigue resistance more effectively than an endurance training program. 20 20 10 Recovery from fatigue The faster component is due to reversal of the metabolic changes which caused fatigue in the first place; for example, wash-out potassium ions and restoration of the phosphocreatine store which will take up the excess of phosphate ions. These processes are relatively fast and are completed in minutes. There remains a second component of fatigue which recovers much more slowly, taking several days for muscles to regain their normal capacity. In real life we will experience this as ‘heavy’ legs: we can perform almost normally but this requires markedly more mental effort 21 21 Recovery from fatigue Experiments on isolated muscles suggest that this delayed recovery is also caused by reduced Ca2+ release (Point 4) The action potential is normal and the SR is normally loaded with Ca2+ but the coupling between the action potential and Ca2+ release is damaged (point 3). Calpain 1 has digested the EC coupling protein 22 22 11 Recovery from fatigue This delayed recovery is likely to be an important cause of overtraining, which is seen in many sports. Many athletes and coaches believe that the more you train, the better you perform. However, there is a limit to the beneficial effects of training. With too much training the slow phase of recovery is never completed and performance can start to decline. Some athletes respond to this decline by training even more and a vicious cycle develops. Nevertheless, there is wide recognition of this problem and it is one of the factors which underlies the practise of ‘tapering’ of training adopted by most athletes before big events. 23 23 Summary The answer to the question ‘What causes muscle fatigue?’ Is ‘It depends on the type of activity” Note: we have not mentioned the role of free radicals or chloride. For more details read the two references given in the next slide. 24 24 12 Further reading Much of this lecture was sourced from and based on the two following publications. 1. Allen DG, Lamb GD, Westerblad H. Impaired calcium release during fatigue. J Appl Physiol 104: 296–305, 2008. 2. Allen DG, Lamb GD, Westerblad H. Skeletal muscle fatigue: cellular mechanisms. Physiol Rev 88: 287–332, 2008. 25 25 13