Ca-CaM-AMPK signaling models

Introduction

Calcium (Ca²⁺) plays a pivotal role in almost all cellular processes and ensures the functionality of an organism. In skeletal muscle fibers, Ca²⁺ is critically involved in the innervation of skeletal muscle fibers that results in the exertion of an action potential along the muscle fiber membrane, the prerequisite for skeletal muscle contraction. Furthermore and among others, Ca²⁺ regulates also intracellular processes, such as myosin-actin cross bridging, protein synthesis, protein degradation and fiber type shifting by the control of Ca²⁺-sensitive proteases and transcription factors, as well as mitochondrial adaptations, plasticity and respiration. These data highlight the overwhelming significance of Ca²⁺ ions for the integrity of skeletal muscle tissue. While the fast and acute oscillation of free Ca²⁺ levels in skeletal muscle is the major step in initiation of muscle contraction and relaxation, slower shifts of cytosolic Ca²⁺ levels are important contributors in the regulation of skeletal muscle plasticity by activation of specific signaling pathways such as the calmodulin/calcineurin signaling pathway (Gehlert et al., 2015) [1]. Computational modelling is likely to play an important role in analysing the quantitative behaviour of such pathways, in turn providing data for the basis of potential therapeutic drug design. On this page we would like to summarize all developed mathematical models dedicated to this topic of the research.

Ca-CaM-AMPK signaling pathway

The orchestra of Ca²⁺ signaling mechanisms in skeletal muscle determines a multitude of cellular processes. Already the initiation of muscle contraction at the neuromuscular junction is a Ca²⁺-dependent process at the motor endplate inducing a change in membrane polarization and a subsequent opening of L-type Ca²⁺ channels triggering the release of Ca²⁺ from the sarcoplasmatic reticulum (SR). This mechanism allows a distinct rise of cytosolic Ca²⁺ concentration that initiates actin/myosin interaction and movement of the myosin head. To facilitate the interplay of contraction and relaxation the SR is provided by several Ca²⁺ transport and binding molecules which are adjusted by a multitude of regulatory molecules. ATP production and hence energy supply of contracting muscle is also regulated by Ca²⁺-dependent enhancement of glycolytic enzyme activity and mitochondrial respiration. The high plasticity of skeletal muscle is enabled by Ca²⁺-dependent regulation of gene expression, translation and posttranslational processes including protein degradation.

References

1. Gehlert S, Bloch W, and Suhr F. Ca2+-dependent regulations and signaling in skeletal muscle: from electro-mechanical coupling to adaptation. Int J Mol Sci. 2015 Jan 5;16(1):1066-95. DOI:10.3390/ijms16011066 |
2. Kunz WS. Control of oxidative phosphorylation in skeletal muscle. Biochim Biophys Acta. 2001 Mar 1;1504(1):12-9. DOI:10.1016/s0005-2728(00)00235-8 |
3. Gonzalez-Freire M, Semba RD, Ubaida-Mohien C, Fabbri E, Scalzo P, Højlund K, Dufresne C, Lyashkov A, and Ferrucci L. The Human Skeletal Muscle Proteome Project: a reappraisal of the current literature. J Cachexia Sarcopenia Muscle. 2017 Feb;8(1):5-18. DOI:10.1002/jcsm.12121 |
4. Li Y, Lai N, Kirwan JP, and Saidel GM. Computational Model of Cellular Metabolic Dynamics in Skeletal Muscle Fibers during Moderate Intensity Exercise. Cell Mol Bioeng. 2012 Mar;5(1):92-112. DOI:10.1007/s12195-011-0210-y |
5. Li Y, Solomon TP, Haus JM, Saidel GM, Cabrera ME, and Kirwan JP. Computational model of cellular metabolic dynamics: effect of insulin on glucose disposal in human skeletal muscle. Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1198-209. DOI:10.1152/ajpendo.00713.2009 |