Role of parvalbumin in fatigue-induced changes in force and cytosolic calcium transients in intact single mouse myofibers.

One of the most important cytosolic Ca buffers present in mouse fast-twitch myofibers, but not in human myofibers, is parvalbumin (PV). Previous work using conventional PV gene () knockout (PV-KO) mice suggests that lifelong ablation increases fatigue resistance, possibly due to compensations in mitochondrial volume. In this work, ablation was induced only in adult mice (PV-KO), and contractile and cytosolic Ca responses during fatigue were studied in isolated muscle and intact single myofibers. Results were compared with control littermates (PV-Ctr). We hypothesized that the reduced myofiber cytosolic Ca buffering developed only in adult PV-KO mice leads to a larger cytosolic free Ca concentration ([Ca]) during repetitive contractions, increasing myofiber fatigue resistance. Extensor digitorum longus (EDL) muscles from PV-KO mice had higher force in unfused stimulations (∼50%, < 0.05) and slowed relaxation (∼46% higher relaxation time, < 0.05) versus PV-Ctr, but muscle fatigue resistance or fatigue-induced changes in relaxation were not different between genotypes ( > 0.05). In intact single myofibers from flexor digitorum brevis (FDB) muscles, basal and tetanic [Ca] during fatiguing contractions were higher in PV-KO ( < 0.05), accompanied by a greater slowing in estimated sarcoplasmic reticulum (SR) Ca-pumping versus PV-Ctr myofibers (∼84% reduction, < 0.05), but myofiber fatigue resistance was not different between genotypes ( > 0.05). Our results demonstrate that although the estimated SR Ca uptake was accelerated in PV-KO, the total energy demand by the major energy consumers in myofibers, the cross-bridges, and SR Ca ATPase were not altered enough to affect the energy supply for contractions, and therefore fatigue resistance remained unaffected. Parvalbumin (PV) is a cytosolic Ca buffer that is present in mouse myofibers but not in human muscle. We show that inducible knockout of leads to increases in myofiber cytosolic free Ca concentrations and slowing of Ca pumping during fatigue versus control mice. However, ablation does not interfere with fatigue-induced slowing in relaxation or fatigue resistance. These data support the use of mouse muscle as a suitable model to investigate human muscle fatigue.