Increased resistance to fatigue in creatine kinase deficient muscle is not due to improved contractile economy

Abstract

There has been speculation on the origin of the increased endurance of skeletal muscles in creatine kinase (CK)-deficient mice. Important factors that have been raised include the documented increased mitochondrial capacity and alterations in myosin heavy chain (MyHC) isoform composition in CK-deficient muscle. More recently, the absence of inorganic phosphate release from phosphocreatine hydrolysis in exercising CK-deficient muscle has been postulated to contribute to the lower fatigueability in skeletal muscle. In this study, we tested the hypothesis that the reported shift in MyHC composition to slower isoforms in CK-deficient muscle leads to a decrease in oxygen cost of twitch performance. To that aim, extensor digitorum longus (EDL) and soleus (SOL) muscles were isolated from wild-type (WT) and knock-out mice deficient in the cytoplasmic muscle-type and sarcomeric mitochondrial isoenzymes of CK, and oxygen consumption per twitch time-tension-integral (TTI) was measured. The results show that the adaptive response to loss of CK function does not involve any major change to contractile economy of skeletal muscle.

Gated dynamic 31P MRS shows reduced contractile phosphocreatine breakdown in mice deficient in cytosolic creatine kinase and adenylate kinase

“…However, as explained above, large changes in overall fibre type are unlikely to have occurred in our mice, at least to an extent sufficient to influence the result of muscle contractions of the whole calf muscle complex. Furthermore, in mice lacking muscle CK, fast muscles that have adapted to resemble a slower fibre type did not show an improved contractile economy during twitch contractions (31). Finally, in AK deficient mice the ATP cost per contraction is increased (32), indicating a decreased contractile economy in contrast to an increased economy.…”

“…In mice lacking MM-CK and mice lacking both muscle isoforms of CK, altered Ca 2þ kinetics have been observed (26) and it is possible that the increased muscle relaxation times in MAK À/À mice originate from similar problems in Ca 2þ handling. 31…”

“…Multiple isoforms of the AK enzyme are expressed in skeletal muscles and the AK1 variant is considered the most important (representing approximately 99% of all AK activity) (5). 31 P MR spectroscopy (MRS) is a valuable non-invasive technique to assess energy metabolism in skeletal muscles in vivo, and can be used to investigate various enzymatic reactions, in particular the CK reaction. The technique is most powerful when used to monitor the metabolic effects of contraction and recovery thereof, especially if combined with the measurement of contractile performance.…”

“…31 P MR spectra of a WT mouse (left) and an MAK À/À mouse (right) before the stimulation protocol (bottom), shortly after contraction (middle) and 25 s after contraction (top). Notice the decrease in PCr in the WT mouse shortly after contraction, which is absent in the MAK À/À mouse.…”

Fiber-type-specific sensitivities and phenotypic adaptations to dietary fat overload differentially impact fast- versus slow-twitch muscle contractile function in C57BL/6J mice

“…Tetanic contractions were evoked at 90 Hz for EDL (train duration 0.5 s) and 50 Hz for soleus (train duration 1.5 s), which are typical fusion frequencies for these muscles at 20°C [22]. Muscles were allowed to recover for 10 min between different stimulation protocols.…”