The extended, dynamic mitochondrial reticulum in skeletal muscle and the creatine kinase (CK)/phosphocreatine (PCr) shuttle are working hand in hand for optimal energy provision.

Abstract

The existence of a mitochondrial reticulum or network was postulated already in 1986 (Kirkwood et al. 1986) and the effect of endurance training on the fine structure of this very reticulum was documented in the following year (Kirkwood et al. 1987). A decade later the concept of mitochondrial networks in skeletal muscle definitely gained support by improved techniques, using a detailed ultra-structural analysis of ultrathin cryo-sections of human muscle by electron microscopy (Ogata and Yamasaki 1997). Now, in their letter on ‘‘Mitochondrial reticulum for cellular energy distribution in muscle’’ the authors Glancy et al. with Balaban (Nature 523:617–620, 2015) presented very elegant and technically brilliant work corroborating the existence of a mitochondrial reticulum network inside skeletal muscle fibers. In addition, these authors provide new evidence that this mitochondrial reticulum network provides a conductive pathway for energy distribution and helps to minimize diffusion distances for metabolites such as ATP. The authors propose that mitochondrial membrane potential conduction via this mitochondrial reticulum is the dominant pathway for energy distribution in skeletal muscle and that the phospho-creatine (PCr)/kinase creatine kinase (CK) shuttle (Bessman and Geiger 1981; Wallimann et al. 1992) would not be critical for normal muscle function. In their discussion it is stated, however, that CK would probably still provide a significant evolutionary advantage, justifying the retention or development of the system (Glancy et al. 2015). As a matter of fact, evolutionarily the phosphagen kinase system dates back several hundred millions of years to early metazoan CK (Uda et al. 2012) or even bacteria with arginine kinase (AK) (Suzuki et al. 2013). To support the interpretation of their data, the authors argue that the skeletal muscle phenotypes of CK knock-out or creatine(Cr)-deficiency mice are small with nearly normal muscle function and that only modest adaptations are seen in these transgenic animals. Unfortunately, both statements are incorrect. First, at a closer look, the phenotype of the CK double knock-out mouse is physiologically relevant in terms of muscle force and relaxation (Steeghs et al. 1997), and CK injection into CK-deficient skeletal muscle fibers restores contractile function and calcium handling (Dahlstedt et al. 2003) that are both distinctly disturbed in the CK double knock-outs lacking expression of cytosolic muscle MM-CK as well as mitochondrial mtCK (Steeghs et al. 1997; 1998). Even skeletal muscles of mice that are deficient only in cytosolic MM-CK clearly lack muscle burst activity (van Deursen et al. 1993) and down-regulated expression of MM-CK in skeletal muscle of transgenic mice leads to a correspondingly lowered ability to perform muscle contractile burst activity that closely correlates with the level of MM-CK expression (Van Deursen et al. 1994). Second, the adaptation changes observed in skeletal muscle due to abrogation of the CK system are astonishing, e.g. the mitochondrial content in fast-type glycolytic muscles (normally devoid of intra-myofibrillar mitochondria) of these transgenic animals is highly up-regulated and the appearance of these transformed muscles lacking CK rather resemble oxidative insect endurance flight muscles with a very high mitochondrial content and a vast propensity of intra-myofibrillar mitochondria (van Deursen et al. 1993, see Fig. 2; and Steeghs et al. 1997, see Fig. 4) with a corresponding mitochondrial network. Most relevant with respect to muscle pathology is the observed formation & Theo Wallimann theo.wallimann@cell.biol.ethz.ch