Combined myofibrillar and mitochondrial creatine kinase deficiency impairs mouse diaphragm isotonic function

Abstract

atine kinase deficiency impairs mouse diaphragm isotonic function. J. Appl. Physiol. 82(5): 1416-1423,1997.-Creatine kinase (CK) is an enzyme central to cellular high-energy phosphate metabolism in muscle. To characterize the physi ological role of CK in respiratory muscle during dynamic contractions, we compared the fore e-velocity relationships, power, and work output characteristics of the diaphragm (Dia) from mice with combined myofibrillar and sarcomeric mitochondrial CK deficiency (CK [-7-]) with CK-sufficient controls (Ctl). Maximum velocity of shortening was signifi cantly lower in CK[-/-] Dia (14.1 ± 0.9 L Js7 where L0 is optimal fiber length) compared with Ctl Dia (17.5 ± 1.1 LJs) (P < 0.01). Maximum power was obtained at 0.4-0.5 tetanic force in both groups; absolute maximum power (2,293 ± 138 W/m2) and work (201 ± 9 J/m2) were lower in CK[-/ -] Dia compared with Ctl Dia (2,744 ± 146 W/m2 and 284 ± 26 J/m2, respectively) (P < 0.05). The ability of CK [-/-] Dia to sustain shortening during repetitive isotonic activation (75 Hz, 330-ms duration repeated each second at 0.4 tetanic force load) was markedly impaired, with CK[-/-] Dia power and work declining to zero by 37 ± 4 s, compared with 61 ± 5 s in Ctl Dia. We conclude that combined myofibrillar and sarcomeric mitochondrial CK deficiency profoundly impairs Dia power and work output, underscoring the functional importance of CK during dynamic contractions in skeletal muscle. respiratory muscle; fatigue; myosin heavy chain r e s p i r a t o r y MUSCLE FATIGUE is a phenom enon of clini cal im portance contributing to the development of ventilatory failure in neonates and adults. The factors predisposing muscle to fatigue are felt prim arily to resu lt from an im balance betw een energy supply and dem and (25, 35). The accum ulation of energy m etabo lites in all probability also plays an im portant role (1,6,8). A lteration of th e capacity of skeletal muscle to produce or sustain ATP levels is th u s likely to affect muscle fatigue resistance. C reatine kinase (CK), an enzyme central to cellular high-energy phosphate m e tabolism in muscle, m ay be im p o rtan t in this regard. CK catalyzes the following reaction PC r +MgAJDP-+ H + <=> Cr + MgATP2" where PC r is phosphocreatine and Cr is creatine. The high level of CK activity found in skeletal muscle ensures th at, w hen consistent high-energy phosphate production is necessary during repetitive contractile activity, ATP levels will be m aintained at the expense of PCr. This role of CK as an ATP buffer is widely accepted (18, 33).Defining a physiological role for CK in skeletal muscle fatigue, however, has been difficult, with prior studies using substrate analogs (10,16,17,20) of Cr to assess the functional consequences of impaired CK activity. These studies have generated disparate re sults and exclusively examined fatigue under repetitive isometric conditions. The respiratory muscles' capacity to sustain ventilation, however, is determined in large p a rt by its ability to shorten and m aintain for...

Functional Equivalence of Creatine Kinase Isoforms in Mouse Skeletal Muscle

“…These results support the idea that only a minimal level of CK is required for proper contractile function independent of localization. Initial results for heart and diaphragm from the M-CK KO mice indicate these tissues function like control, probably due to sufficient amounts of mitochondrial CK (43)(44)(45). Alternatively, it may be that localization of CK to other structures is important and that BB-CK is properly localized.…”

“…For example, MM-CK has been shown to be associated with the sarcoplasmic reticulum, and recent evidence indicates that there are defects in calcium handling in M-CK KO and combined mitochondrial and M-CK KO mice (46). Finally, it is possible that metabolic adaptations substitute for any function of the localized forms of CK (43)(44)(45), although little evidence of adaptation was found in the switch muscle. Rather than serve a specific function, it may be that localization of metabolic enzymes to subcellular structures occurs to avoid macromolecular crowding in general in the cell (47).…”

The “glycogen shunt” in exercising muscle: A role for glycogen in muscle energetics and fatigue

“…Watchko et al (23) created mutant mouse strains missing either or both forms of creatine kinase and compared functional diaphragm muscle performance with controls during isotonic activation. Both singly mutated forms showed no difference from controls in force velocity, power, time of sustained shortening, and work output, whereas in the doubly mutated animal CK [Ϫ͞Ϫ], these were somewhat reduced.…”

Association of muscle-specific creatine kinase (CKMM) gene polymorphism with physical performance of athletes

“…Several studies have demonstrated that the inhibi tion of the M CK activity immediately reduces the intensity and power of muscle contractions [6][7][8][9] and results in enhanced oxygen uptake by the contracting muscles [10].…”