Abstract
The slow calcium transient triggered by low-frequency electrical stimulation (ES) in adult muscle fibers and regulated by the extracellular ATP/IP3/IP3R pathway has been related to muscle plasticity. A regulation of muscular tropism associated with the MCU has also been described. However, the role of transient cytosolic calcium signals and signaling pathways related to muscle plasticity over the regulation of gene expression of the MCU complex (MCU, MICU1, MICU2, and EMRE) in adult skeletal muscle is completely unknown. In the present work, we show that 270 0.3-ms-long pulses at 20-Hz ES (and not at 90 Hz) transiently decreased the mRNA levels of the MCU complex in mice flexor digitorum brevis isolated muscle fibers. Importantly, when ATP released after 20-Hz ES is hydrolyzed by the enzyme apyrase, the repressor effect of 20 Hz on mRNA levels of the MCU complex is lost. Accordingly, the exposure of muscle fibers to 30 μM exogenous ATP produces the same effect as 20-Hz ES. Moreover, the use of apyrase in resting conditions (without ES) increased mRNA levels of MCU, pointing out the importance of extracellular ATP concentration over MCU mRNA levels. The use of xestospongin B (inhibitor of IP3 receptors) also prevented the decrease of mRNA levels of MCU, MICU1, MICU2, and EMRE mediated by a low-frequency ES. Our results show that the MCU complex can be regulated by electrical stimuli in a frequency-dependent manner. The changes observed in mRNA levels may be related to changes in the mitochondria, associated with the phenotypic transition from a fast- to a slow-type muscle, according to the described effect of this stimulation frequency on muscle phenotype. The decrease in mRNA levels of the MCU complex by exogenous ATP and the increase in MCU levels when basal ATP is reduced with the enzyme apyrase indicate that extracellular ATP may be a regulator of the MCU complex. Moreover, our results suggest that this regulation is part of the axes linking low-frequency stimulation with ATP/IP3/IP3R.
Highlights
Skeletal muscle can modify its phenotype to adapt to different external stimuli, such as disuse (Goldspink et al, 1986; Kneppers et al, 2019), hypoxia (Baresic et al, 2014; Nguyen et al, 2016), physical exercise (Yan et al, 2012; Joseph et al, 2016), among others (Gundersen, 2011), in a process known as muscle plasticity
We have demonstrated that low-frequency electrical stimulation (ES) results in a decrease in the mRNA levels of mitochondrial calcium uniporter (MCU), mitochondrial Ca2+ uptake 1 (MICU1), MICU2, and essential MCU regulator (EMRE), while high-frequency ES does not generate modifications
Our laboratory has described a fine-tuned mechanism that relates the decoding of the frequency of stimulation by Cav1.1, adenosine triphosphate (ATP) release, IP3R activation, and transcription changes related to fast-to-slow muscle phenotype transition (Jorquera et al, 2013)
Summary
Skeletal muscle can modify its phenotype to adapt to different external stimuli, such as disuse (Goldspink et al, 1986; Kneppers et al, 2019), hypoxia (Baresic et al, 2014; Nguyen et al, 2016), physical exercise (Yan et al, 2012; Joseph et al, 2016), among others (Gundersen, 2011), in a process known as muscle plasticity. Through activation of NMDA receptor has been described (Qiu et al, 2013) These works reveal the importance of understanding the role that transient changes in cytosolic Ca2+ levels (induced by a physiological stimulus) play in the regulation of gene expression of MCU, MICU1.1, MICU2, and EMRE in a tissue such as skeletal muscle where Ca2+ is a key factor. Such regulation could modulate the Ca2+ buffering efficiency of mitochondria, generating a physiological control loop of intracellular Ca2+. The changes observed appear in line with an asymmetric distribution of some of these proteins between fast and slow phenotype muscle fibers
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