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The energy consumption of skeletal muscle cells mayincrease up to 100-fold when going from rest to high-inten-sity exercise. This high energy demand exceeds the aerobiccapacity of the muscle cells, and a large fraction of the ATPrequired will come from anaerobic metabolism. High-intensityexercise also leads to a rapid decline in contractile functionknown as skeletal muscle fatigue. It therefore seems logicalthat there is a causal relationship between anaerobic metabo-lism and muscle fatigue; that is, some consequence(s) of anaer-obic metabolism causes the decline in contractile function.Anaerobic breakdown of glycogen leads to an intracellularaccumulation of inorganic acids, of which lactic acid is quan-titatively the most important. Since lactic acid is a strong acid,it dissociates into lactate and H+. Lactate ions would have lit-tle effect on muscle contraction (16); however, the increase inH+(i.e., reduced pH or acidosis) is the classic cause of skele-tal muscle fatigue. However, the role of reduced pH as animportant cause of fatigue is now being challenged, and sev-eral recent studies (5, 14, 19, 20) show that reduced pH mayhave little effect on contraction in mammalian muscle at phys-iological temperatures.Besides acidosis, anaerobic metabolism in skeletal musclealso involves hydrolysis of creatine phosphate (CrP) to creatineand inorganic phosphate (Pi). Creatine has little effect on con-tractile function, whereas there are several mechanisms bywhich increased Pimay depress contractile function. Thus, onthe basis of recent findings (68, 1012), increased Piratherthan acidosis appears to be the most important cause of fatigueduring high-intensity exercise. This brief review will outline theresults that form the basis for the switch from acidosis toincreased Pias the major fatigue factor in mammalian muscle.We will focus on studies in which fatigue develops on the timescale of minutes, in which the consequences of anaerobicmetabolism would be of greatest importance. With even moreintense activation (e.g., a continuous maximal contraction),other factors, like failure of action potential propagation, maybecome increasingly important. Conversely, with more long-lasting types of exercise (e.g., marathon running), factors suchas depletion of carbohydrate stores and dehydration becomeincreasingly important.To study the mechanisms underlying fatigue, we frequentlyuse isolated muscle cells (fibers), which are fatigued byrepeated tetani of short duration. The present review will focuson results obtained in such studies as well as studies onskinned muscle fibers (i.e., muscle cells where the surfacemembrane has been chemically or physically removed). This isbecause studies on single muscle fibers provide the most directway to address cellular mechanisms of fatigue. It may beargued that conclusions drawn from studies on single fibers arenot relevant to the fatigue experienced by humans during var-ious types of exercise. However, available data indicate thatthe mechanisms of fatigue are qualitatively similar in diverseexperimental models, ranging from exercising humans to sin-gle fibers (2). The differences that inevitably must exist appearto be mainly of a quantitative nature.The rise and fall of lactic acid as a direct cause of skele-tal muscle dysfunction in fatigueDuring intense muscle activity, the intracellular pH may fallby ~0.5 pH units. There are two major lines of evidence thathave been used to link this decline in pH to the contractile dys-function in fatigue. First, studies on human muscle fatigue haveoften shown a good temporal correlation between the declineof muscle pH and the reduction of force or power production.Second, studies on skinned skeletal muscle fibers have shownthat acidification may reduce both the isometric force and theshortening velocity.However, in humans the temporal correlation betweenimpaired contractile function during fatigue and reduced pH isnot always present. For instance, force sometimes recoversmore rapidly than pH after the end of fatiguing contractions(18). This means that if reduced pH has a direct force-depress-ing effect in human muscles, this effect must have been coun-teracted by some other factor that increases force to the sameextent. Such a force-potentiating factor has not been identified,and hence the obvious conclusion is that there is no causalrelationship between acidosis and reduced force production.Important evidence in favor of acidosis causing reducedforce production comes from studies on skinned muscle fibersthat were performed at @15°C (14). Recent studies havefocused on the temperature dependence of the pH effects onforce, and the results of these studies further challenge the roleof H+in mammalian muscle fatigue. Some early studies con-170886-1714/02 5.00 © 2002 Int. Union Physiol. Sci./Am.Physiol. Soc.News Physiol. Sci. • Volume 17 • February 2002Muscle Fatigue: Lactic Acid or Inorganic Phos-phate the Major Cause?Håkan Westerblad,1David G. Allen,2and Jan Lännergren11Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; and 2Department of Physiology and Institute of Biomed-ical Research, University of Sydney F13, New South Wales 2006, AustraliaIntracellular acidosis due mainly to lactic acid accumulation has been regarded as the most impor-tant cause of skeletal muscle fatigue. Recent studies on mammalian muscle, however, show littledirect effect of acidosis on muscle function at physiological temperatures. Instead, inorganicphosphate, which increases during fatigue due to breakdown of creatine phosphate, appearsto be a major cause of muscle fatigue.ducted more than 10 years ago showed that acidification, ifanything, resulted in an increased tetanic force at physiologi-cal temperatures (17). More recently, Pate and colleagues (14)studied skinned rabbit psoas fibers and observed the expectedlarge depressive effect of lowered pH at 10°C, but the effect ofacidification on force production was small at 30°C. Similarresults have subsequently been obtained in isolated singlemouse muscle fibers (19) and whole mouse muscles (20) (Fig.1A).Acidification has been considered to be an important factorbehind the reduced shortening speed in fatigue. However,using skinned rabbit muscle fibers, Pate and colleagues (14)showed that acidification has little effect on the shorteningspeed at 30°C. Similarly, in intact mouse muscle fibers, themaximum shortening velocity was reduced by


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UA ECOL 437 - Study Notes

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