Ryanodine receptor leak triggers fiber Ca ²⁺ redistribution to preserve force and elevate basal metabolism in skeletal muscle

Abstract

Muscle contraction depends on tightly regulated Ca 2+ release. Aberrant Ca 2+ leak through ryanodine receptor 1 (RyR1) on the sarcoplasmic reticulum (SR) membrane can lead to heatstroke and malignant hyperthermia (MH) susceptibility, as well as severe myopathy. However, the mechanism by which Ca 2+ leak drives these pathologies is unknown. Here, we investigate the effects of four mouse genotypes with increasingly severe RyR1 leak in skeletal muscle fibers. We find that RyR1 Ca 2+ leak initiates a cascade of events that cause precise redistribution of Ca 2+ among the SR, cytoplasm, and mitochondria through altering the Ca 2+ permeability of the transverse tubular system membrane. This redistribution of Ca 2+ allows mice with moderate RyR1 leak to maintain normal function; however, severe RyR1 leak with RYR1 mutations reduces the capacity to generate force. Our results reveal the mechanism underlying force preservation, increased ATP metabolism, and susceptibility to MH in individuals with gain-of-function RYR1 mutations.

A controversial issue: Can mitochondria modulate cytosolic calcium and contraction of skeletal muscle fibers?

“…(2017) for cardiomyocytes. The recent paper by Lamboley et al (2021) and coworkers has provided the first direct measurement of bound-to-free calcium ratio in mitochondria in FDB muscle fibers, the most used model of intact adult skeletal muscle fibers ex vivo. The total amount of calcium was measured by applying the lysis method, designed by Fryer and Stephenson (1996).…”

Excitation-contraction coupling in mammalian skeletal muscle: Blending old and last-decade research

“…For instance, as discussed (Section 3.1), a peak [Ca 2+ ] of 0.2-1 μM in mammalian fibres (Launikonis et al, 2009;Koenig et al, 2018) is untrue, and an inaccurate TT [Ca 2+ ] calibration was acknowledged when we compare papers in which estimated values of 100 μM (Launikonis et al, 2009) were updated to be over 1 mM (Cully et al, 2016). Another option, if all mentioned SOCE estimates turn true (then, ruling out any role in SR refilling or sarcoplasmic [Ca 2+ ] maintenance), and that the rate of exchange of Ca 2+ with the tubules is low (Lamboley et al, 2021), is that SOCE in skeletal muscle may be, under certain conditions, a custodian of the fibre total amount of Ca 2+ . Although complete models considering the internal equilibrium of Ca 2+ have already been presented (Section 3.1), models regarding its external equilibrium remain a pending task.…”

Mutations in proteins involved in E-C coupling and SOCE and congenital myopathies

“…The further characterization of these mouse models revealed that, in addition to inducing alterations in muscle contraction and/or structure, these RYR1 mutations can impact on other aspects of muscle biology that were not previously considered. For example, extracellular Ca 2+ entry was shown to be altered in some of these mouse models, and it was proposed that this may contribute, in the short or long term, to exacerbate muscle impairment ( Yang et al, 2007 ; Cherednichenko et al, 2008 ; Bannister et al, 2010 ; Estève et al, 2010 ; Eltit et al, 2013 ; Yarotskyy et al, 2013 ; Lamboley et al, 2021 ). In Ryr1 G2434R/WT and Ryr1 T4826I/WT mice, the decrease in SR Ca 2+ content due to channel leakage activates SOCE and increases mitochondrial Ca 2+ uptake ( Yang et al, 2007 ; Lamboley et al, 2021 ).…”

“…For example, extracellular Ca 2+ entry was shown to be altered in some of these mouse models, and it was proposed that this may contribute, in the short or long term, to exacerbate muscle impairment ( Yang et al, 2007 ; Cherednichenko et al, 2008 ; Bannister et al, 2010 ; Estève et al, 2010 ; Eltit et al, 2013 ; Yarotskyy et al, 2013 ; Lamboley et al, 2021 ). In Ryr1 G2434R/WT and Ryr1 T4826I/WT mice, the decrease in SR Ca 2+ content due to channel leakage activates SOCE and increases mitochondrial Ca 2+ uptake ( Yang et al, 2007 ; Lamboley et al, 2021 ). This is, initially, translated into activation of a preserving mechanism that leads to increased ATP production to support the greater demand of ATP exerted by SERCA pumps in their continuous activity to counteract Ca 2+ leak ( Lamboley et al, 2021 ).…”

“…In Ryr1 G2434R/WT and Ryr1 T4826I/WT mice, the decrease in SR Ca 2+ content due to channel leakage activates SOCE and increases mitochondrial Ca 2+ uptake ( Yang et al, 2007 ; Lamboley et al, 2021 ). This is, initially, translated into activation of a preserving mechanism that leads to increased ATP production to support the greater demand of ATP exerted by SERCA pumps in their continuous activity to counteract Ca 2+ leak ( Lamboley et al, 2021 ). Nevertheless, in the long term, mitochondria from both Ryr1 G2434R/WT and Ryr1 T4826I/WT mice showed structural and functional alterations, mainly in fatty acid metabolisms, that resulted in lipotoxicity and an increase in oxidative stress, impacting muscle bioenergetics and muscle performance ( Yuen et al, 2012 ; Chang et al, 2020 ).…”