Abstract
Variations of free calcium concentration ([Ca2+]) are powerful intracellular signals, controlling contraction as well as metabolism in muscle cells. To fully understand the role of calcium redistribution upon excitation and contraction in skeletal muscle cells, the local [Ca2+] in different compartments needs to be taken into consideration. Fluorescent probes allow the determination of [Ca2+] in the cytosol where myofibrils are embedded, the lumen of the sarcoplasmic reticulum (SR) and the mitochondrial matrix. Previously, models have been developed describing intracellular calcium handling in skeletal and cardiac muscle cells. However, a comprehensive model describing the kinetics of the changes in free calcium concentration in these three compartments is lacking. We designed a new 3D compartmental model of the half sarcomere with radial symmetry, which accounts for diffusion of Ca2+ into the three compartments and simulates its dynamics at rest and at various rates of stimulation in mice skeletal muscle fibers. This model satisfactorily reproduces both the amplitude and time course of the variations of [Ca2+] in the three compartments in mouse fast fibers. As an illustration of the applicability of the model, we investigated the effects of Calsequestrin (CSQ) ablation. CSQ is the main Ca2+ buffer in the SR, localized in close proximity of its calcium release sites and near to the mitochondria. CSQ knock-out mice muscles still preserve a near-normal contractile behavior, but it is unclear whether this is caused by additional SR calcium buffering or a significant contribution of calcium entry from extracellular space, via stored-operated calcium entry (SOCE). The model enabled quantitative assessment of these two scenarios by comparison to measurements of local calcium in the cytosol, the SR and the mitochondria. In conclusion, the model represents a useful tool to investigate the impact of protein ablation and of pharmacological interventions on intracellular calcium dynamics in mice skeletal muscle.
Highlights
The cytosolic calcium concentration ([Ca2+]cyto) plays a crucial role in the regulation of muscle contraction and relaxation [1]
The calcium-mediated regulation is critically dependent on the calcium release units (CRUs), the specialized intracellular junctions, named triads, which are formed by the apposition of the terminal cisternae (TC) of the sarcoplasmic reticulum (SR) and the transverse tubuli (TT)
As a further test and an illustration of the applicability of the model we investigated the effects of Calsequestrin (CSQ) ablation
Summary
The cytosolic calcium concentration ([Ca2+]cyto) plays a crucial role in the regulation of muscle contraction and relaxation [1]. The intermyofibrillar mitochondria are located near to the CRUs. Among the most important proteins composing the CRUs there are the dihydropiridine receptor (DHPR), acting as a voltage sensor, the ryanodine receptor (RyR), which is the TC calcium release channel, the SR Ca2+ buffer calsequestrin (CSQ), and the junctional proteins triadin and junctin. Among the most important proteins composing the CRUs there are the dihydropiridine receptor (DHPR), acting as a voltage sensor, the ryanodine receptor (RyR), which is the TC calcium release channel, the SR Ca2+ buffer calsequestrin (CSQ), and the junctional proteins triadin and junctin Mutations of these proteins are known to cause severe disorders and diseases, such as Malignant Hyperthermia (MH), Central Core Disease (CCD), and Vacuolar Myopathy (see for recent reviews [2,3])
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