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Molecular and Cellular Adaptation of Muscle in Response to e

Molecular and Cellular Adaptation of Muscle in Response to e

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PHYSIOLOGICAL REVIEWSVol. 71, No. 2, April 1991Printed in U.S.A.
Molecular and Cellular Adaptation of Muscle in Responseto Exercise: Perspectives of Various Models
FRANK W. BOOTH AND DONALD B. THOMASONDepartment
of
Physiology
and
Cell Biology, University of Texas Medical School, Houston, Texas; andDepartment of Physiology and Biophysics, University
of
Tennessee Medical School, Memphis, TennesseeI. Physiological Significance ........................................................................... 541A. Significance of adaptations to environment ..................................................... 541B. Significance of adaptations to exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542C. Causes of fatigue in skeletal muscle during physical exercise .................................. 542II. Classification of Models Closely Mimicking Human Physical Activity and Models of IncreasedContractile Activity That Do Not Mimic Human Exercise .................................... 544A. Human physical activity ......................................................................... 544B. Animal models that closely mimic human physical activity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544C. Animal models of increased contractile activity that do not mimic human physical activity . 544D. Increased contractile activity in tissue cultures of muscle cells ................................ 545E. Terminology......................................................................................545III. Response of Cellular Processes in Skeletal Muscle to Single Bout of Exercise .................... 545A. Glucose uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 545B. Malonyl-coenzyme A ............................................................................. 547C. Sarcoplasmic reticulum .......................................................................... 547IV. Adaptation of Skeletal Muscle to Repeated Bouts of Aerobic Exercise ............................ 547A. Mitochondria ..................................................................................... 547B. Glycolytic enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 553C. Lactate dehydrogenase .......................................................................... 555D. Myosin isoform switching ....................................................................... 556E. Oxygen flux ....................................................................................... 559V. Adaptation of Skeletal Muscle to Repeated Bouts of Resistance Exercise ......................... 560A. Human physical activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 560B. Animal models mimicking human heavy-resistance training ..................................560C. Adaptations differ in aerobic and strength training ............................................ 561VI. Hypertrophy in Animal Models Not Mimicking Human Physical Activity ........................ 561A. Adaptations differ between certain animal models and humans ............................... 561B. Animal models of stretch-induced hypertrophy ................................................ 562C. Animal models of compensatory overload-induced hypertrophy ............................... 563VII. Muscles or Muscle Cells in Culture Do Not Mimic Human Physical Activity ..................... 564VIII. Regrowth of Atrophied Skeletal Muscle ............................................................ 565IX. Summary of Inferred Sites for Gene Expression in Those Animal Models That Closely MimicHuman Physical Activity ....................................................................... 566X. Adaptations That Affect Cardiac Output ........................................................... 566A. Stroke volume adaptations ...................................................................... 567B. Chronotropic adaptations ........................................................................ 572XI. Adaptations That Affect Cardiac and Peripheral Blood Flow ...................................... 573A. Coronary blood flow . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573B. Muscle blood flow ................................................................................ 573XII. Adaptations That Affect Cardiac Myocyte Metabolism ............................................ 574A. Substrate metabolism ............................................................................ 574B. Oxidative phosphorylation ....................................................................... 574XIII. Conclusion ........................................................................................... 574I. PHYSIOLOGICAL SIGNIFICANCE
for adaptation to changes in the environment likely
A. SigniIcance of Adaptations to Environment
carry over to some of the adaptations occurring becauseof physical training. Prosser (316,317) has written thatThe ability of an animal to adapt to repeated boutscellular, organ, and systemic alterations that favor sur-of physical exercise over a period of weeks such that viva1 of an animal to an environmental change are saidexercise capacity is improved is termed physical train- to be adaptive. Physical exercise, like environmentaling. Some of the inherent mechanisms that are crucial change, disrupts the milieu interieur. Fisher (103) has
0031-9333/91 $1.50 Copyright 0 1991 the American Physiological Society 541
 
542
FRANK W. BOOTH AND DONALD B. THOMASON Volume
71
emphasized that biochemical and physiological adapta-tions to a changed environment or physiological stimu-lus fall into two categories based on their duration. Cel-lular, organ, or systemic alterations that occur on thesame time scale as a single exercise bout are said to beacute exercise responses. On the other hand, changes incells, organs, or systems that persist for appreciable pe-riods after or as a consequence of physical training aresaid to be exercise adaptations. A function of exerciseadaptation seems to be to minimize disruption of homeo-stasis during an exercise bout. It is this better mainte-nance of the milieu interieur by the exercise adaptationsthat favors the functional effectiveness of the animalbeyond the resting state. Less disruption in homeostasispermits the animal or human to undergo physical workfor longer durations at the same absolute power beforefatigue. This review considers molecular and cellular re-sponses to exercise that may signal molecular and cellu-lar adaptations during physical training.
B. Signijicance of Adaptations to Exercise
This review is organized to use some of the knowncauses of fatigue during physical exercise as links be-tween molecular and cellular changes that occur as aresult of physical training and the chronic adaptationsthat are characteristic of physical training. One canspeculate that adaptations that improved an animal’swork capacity enhanced its survival. The genetic abilityto alter exercise performance through physical traininghas not been lost along the evolutionary scale. Conse-quently, not all known molecular and cellular changes toexercise are considered here; this is because their func-tion may not yet be recognized to be associated withadaptations that ameliorate fatigue. In addition, thisreview does not repeat in great detail material that isavailable in other reviews. There are 11,689 documentsfor the Medline MESH word “exertion,” Medline’s termfor exercise, between 1984-1989, inclusive. To the readerunfamiliar with the causes of fatigue during physical-exertion, enough description has been given (Table 1) topermit understanding of the physiological significanceof the molecular and cellular events. A more detailedreview on fatigue is available (108). In addition, thereader is referred to earlier reviews that have compre-hensively documented biochemical responses to a singleexercise bout and biochemical adaptations of muscle tophysical training.
C. Causes of Fatigue in Skeletal Muscle DuringPhysical Exercise
Fatigue is defined as the inability of the animal orhuman to continue working at a given exercise intensity.Thus a reduction in power output is seen as fatigue(291). This section briefly delineates how various causesof fatigue (Table 1) prevent an animal or a human frombeing able to continue working at a given rate or level ofactivity. Fatigue mechanisms thus cause an individualeither to exercise at a lower intensity or to stop exercis-ing altogether. The reader is referred to an excellentreview by Gollnick (132) for a more in-depth coverage ofenergy metabolism during prolonged exercise.
I. Adenosine triphosphate depletion
The interaction of the myosin and actin filamentsduring muscle contraction is powered by ATP. Througha complex series of molecular events, energy from thebinding and enzymatic cleavage of ATP to ADP and Pipowers the formation of the myosin-actin cross bridge,conformational translocation of the opposing filaments,and release of the cross bridge to begin the cycle again.Thus each cycle of myosin and actin cross-bridge forma-tion consumes an ATP molecule. Furthermore, the pul-satile increase in sarcoplasmic free Ca2+ during contrac-tion initiates cross-bridge cycling; additional ATP isconsumed in releasing and sequestering Ca2’. New-sholme and Leech (291) speculate that the small de-creases in ATP concentration in skeletal muscle duringan all-out sprint would diminish myosin adenosinetri-phosphatase (ATPase) activity and hence cross-bridgecycling, in turn preventing continued sprinting at thesame pace. Also a decreased ATP concentration woulddecrease Ca2’ cycling and possibly contribute to fatigue.
2. LowpH
After continuous high-intensity exercise to exhaus-tion, intramuscular pH can decrease to 6.6-6.3 (171,274,336). In working muscle, the decrease in muscle power(work per unit of time) at low pH is attributed to protoninterference with the catalytic activity of many en-zymes (292). Increased free H+ could produce some, orall, of the following metabolic processes. They are inhibi-tion of phosphofructokinase activity
(74, 135, ZZO),
which would diminish ATP production via glycolysis;decrease of glycogen breakdown by inhibition of phos-phorylase kinase and adenylate cyclase activity and by ashift from HPOZ- to H,PO, (59); decrease in maximumtension due to increased free Ca2’ required to obtain thesame submaximal tension (86); increase in the constantfor. the apparent binding of Ca2’ to troponin (117),thereby attenuating the contractile response (223); anddecrease in Ca2+ release from the sarcoplasmic reticu-lum (289), which would decrease muscle tension. For fur-ther discussions on muscle fatigue, see References 108,153,291,328,336, and 414.Force production by muscle is also reduced by theformation of the diprotonated form of Pi (H,P0,)(295).Because Pi and H+ both increase in muscle undergoingintense exercise, the shift in equilibrium causes force todecrease.
3. Glycogen depletion
A relationship between carbohydrate depletion andfatigue was demonstrated by Christensen and Hansen
 
April 1991 EXERCISE TRAINING ADAPTATIONS
543
TABLE
1. Fatigue types and characteristics, causes, adaptations to delay fatigue onset during exercise, biochemicalbasis of adaptation, and molecular/cellular signals implicated in adaptation
Some Typesof Fatigue
Time to
Fatigue
Energy From, %
Anaerobic Aerobic
Cause of
FatigueAdaptive Strategiesto Delay FatigueBiochemical Basisof AdaptationMolecular andCellular ResponsesSignalingAdaptationAll-out runningsprint of100 mAll-out 1,500-mrunMarathon runof 26 milesLifting heavyobjects-10 s 100 0 ATP and CP Deplete less ATPdepletionper unit of power-4 min 35 65 High PiLow pHLess reliance onglycolysisLess increasein muscle andblood lactateconcentrationsCarbohydratesparing-2h 0 100 GlycogendepletionMaximal O2flux-1 min 100 0 Insufficientmass ofskeletalmuscleIncreased maximalstroke volumeand cardiacoutputIncreased O2 fluxthrough skeletalmuscleIncrease mass ofcontractileprotein inskeletal muscleATP resynthesisprocesses; moreefficient use of ATPIncreased mitochondriaIncreased mitochondriaDecreased glycolyticenzymesImproved Ca2’ influxIncreased blood volumeOther?Increased capillarydensityIncreased myoglobinconcentrationIncreased mitochondria3
?
CAMP? ATP flux?ADP or ATPlevels?CAMP? ATPlevel?ADP or ATP??FGF?CAMP?Other?
?
Fatigue does not derive from a single cause. Thus different human sports have unique sources of fatigue. This table is not inclusive to alltypes of fatigue. Fatigue is defined as a reduction in power output. CP, creatine phosphate; FGF, fibroblast growth factor. [Adapted fromNewsholme (290) and Fitts and Metzger (108).]
in 1939 (61). In this experiment, subjects exercised untilexhaustion, at which time the subjects were hypoglyce-mic. Immediately, 200 g of glucose was given orally.Within 15 min of glucose ingestion, the subjective symp-toms of fatigue were gone, blood glucose had increased,and these subjects were able to exercise for an addi-tional hour. It is possible that central and peripheralnerves, which can only oxidize glucose, are a fatiguingtissue.Later it was shown that the human’s storage of car-bohydrate is limited and is equivalent to +,OOO kcal(56,291). In subjects performing aerobic exercise at 70-100% of aerobic capacity, fatigue occurs at 1-2 h, and itis associated with hypoglycemia (5), depletion of muscleglycogen (4,31,170,355), and depletion of liver glycogen(5,18). The time to exhaustion at these work intensitiesis altered by dietary manipulation of preexercise con-centrations of muscle glycogen; a carbohydrate-poordiet results in the lowest concentrations of muscle gly-cogen and the shortest time for work to fatigue, whereasa carbohydrate-rich diet is associated with the highestconcentration of glycogen and longest work time (31).Numerous strategies involving regulation of sub-strate metabolism can be utilized by exercising organ-isms to conserve carbohydrate stores and thus lengthenthe exercise duration before exhaustion. Theoretically,such adaptive strategies could enhance survivability.Two acute responses to conserve glycogen stores duringaerobic exercise involve I) a shunting of blood glucose toworking skeletal muscle for oxidation and 2) a mobiliza-tion of fatty acid from fat depots, their transport tomuscle, and subsequent oxidation by muscle mitochon-dria. In addition, an adaptive increase in mitochondrialdensity as well as an adaptive decrease in the activitylevels of glycolytic rate-limiting enzymes induced byaerobic training has been shown to play an importantrole in sparing carbohydrate utilization as a fuel duringaerobic exercise. Some of these exercise responses andadaptations are discussed in sections
III
and
IV.
4. Limited maximal oxygen flux
Aerobic training increases maximal oxygen flow(VO2max) (332). To this day, the underlying mecha-nism(s) accounting for the increase in
Voamax
(330) re-mains controversial. Part of the reason for this contro-versy is related to the multiple adaptations that occur inaccordance with the increase in
Vozmax.
Maximal car-diac output, capillary density in skeletal muscle, myoglo-bin concentration in skeletal muscle, and mitochondrialdensity of skeletal muscle all increase in response toaerobic training. Each of these factors is thought to con-tribute to the increase in
Vozmax.
Many researchers in

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