Chronic electrical stimulation of fast-twitch muscle fibers at a frequency consistent with slow-twitch muscle fibers can activate the Ca++-dependent phosphatase calcineurin, which in turn can dephosphorylate NFAT and result in the translocation of NFAT from the myoplasm to the nucleus. This leads to the transcription of slow-twitch muscle genes and inhibition of fast-twitch muscle genes. Overexpression of constitutively active NFAT in fast-twitch muscle promotes the expression of slow-twitch myosin while inhibiting the expression of fast-twitch myosin. The transcription factor myocyte enhancing factor 2 (MEF2) has also been implicated in the transition from fast-twitch to slow-twitch muscle. Activation of MEF2 is thought to occur through Ca++/calmodulin-dependent phosphorylation of the inhibitor of MEF2, histone deacetylase (HDAC).

Intracellular Ca++ plays a crucial role in the expression of the slow myosin isoform. Slow-twitch muscle fibers have a higher resting level of intracellular Ca++ compared to fast-twitch muscle fibers. Additionally, chronic electrical stimulation of fast-twitch muscle is accompanied by a 2.5-fold increase in resting myoplasmic Ca++ before the increased expression of slow-twitch myosin and decreased expression of fast-twitch myosin. Similarly, elevating intracellular Ca++ (approximately fivefold) in muscle cells expressing fast-twitch myosin induces a transition in gene expression from the fast muscle myosin isoform to the slow myosin isoform within 8 days. This transition is accompanied by an increase in citrate synthetase activity (indicative of oxidative capacity) and a decrease in lactate dehydrogenase activity (indicative of glycolytic capacity). These Ca++-dependent changes can be reversed by reducing intracellular Ca++ levels.

Regarding the response to exercise, exercise physiologists categorize training regimens and responses into three categories: learning, endurance, and strength training.
Fig.12.22A ).Specifically,itappearsthatstimulationofadultfast-twitchmusclecellsatafrequencyconsistentwithslow-twitchmusclecellscanactivatetheCa++-dependentphosphatasecalcineurin,whichinturncandephosphorylateNFATandresultintranslocationofNFATfromthemyoplasmtothenucleus,followedbythetranscriptionofslow-twitchmusclegenes(andinhibitionoffast-twitchmusclegenes).Inaccordancewiththismechanism,expressionofconstitutivelyactiveNFATinfast-twitchmusclepromotestheexpressionofslow-twitchmyosinwhileinhibitingtheexpressionoffast-twitchmyosin.Thetranscriptionfactormyocyte enhancing factor 2 (MEF2) hasalsobeenimplicatedinthistransitionfromfast-twitchtoslow-twitchmuscle(see
Fig.12.22B ).ActivationofMEF2isthoughttoresultfromCa++/calmodulin-dependentphosphorylationofaninhibitorofMEF2:namely,histonedeacetylase(HDAC).
Intracellular [Ca++] appears to play an important role in expression of the slow myosin isoform. Slow-twitch muscle fibers have a higher resting level of intracellular Ca++ than do fast-twitch muscle fibers. In addition, chronic electrical stimulation of fast-twitch muscle is accompanied by a 2.5fold increase in resting myoplasmic [Ca++] that precedes the increased expression of slow-twitch myosin and decreased expression of fast-twitch myosin. Similarly, chronic elevation of intracellular Ca++ (approximately fivefold) in muscle cells expressing fast-twitch myosin induces a change in gene expression from the fast muscle myosin isoform to the slow myosin isoform within 8 days. An increase in citrate synthetase activity (an indicator of oxidative capacity) and a decrease in lactate dehydrogenase activity (an indicator of glycolytic capacity) accompany this Ca++-dependent
Muscle: action potential Surface membrane •Fig. 12.22. Molecular Signaling Pathways Contributing to the Transition From Fast-Twitch Muscle to Slow-Twitch Muscle. Chronicelectricalstimulationofafast-twitchmuscleinapatternconsistentwithaslow-twitchmuscleresultsindevelopmentoftheslow-twitchmusclephenotypebecauseofdephosphorylationofthetranscriptionfactornuclearfactorfromactivatedTcells(NFAT)bytheCa++/calmodulin-dependentproteinphosphatasecalcineurin(CaN);thisinturnresultsinnucleartranslocationofNFATandexpressionofslow-twitchmusclefibergenes(A). Activationofthetranscriptionfactormyocyteenhancerfactor2(MEF2)alsoappearstocontributetothisfibertypetransition(B), inwhichactivationofMEF2involvesCa++/calmodulin-dependentphosphorylationofaninhibitor,histonedeacetylase(HDAC).CaMK,Ca++/calmodulin-dependentproteinkinase;ECC,excitation-contractioncoupling;P,phosphorylationofHDAC.(FromLiuY,etal:.Signalingpathwaysinactivity-dependentfibertypeplasticityinadultskeletalmuscle.J Muscle Res Cell Motil. 2005;26:13-21.) transition from fast-twitch to slow-twitch myosin. These Ca++-dependent changes are reversible by a reduction of intracellular [Ca++].
Response to Exercise
Exercise physiologists identify three categories of training regimens and responses: learning, endurance, and strength training (
Table 12.3).