Abstract
Mouse and rat skeletal muscles are capable of a regulatory volume increase (RVI) after they shrink (volume loss resultant from exposure to solutions of increased osmolarity) and that this RVI occurs mainly by a Na-K-Cl-Cotransporter (NKCC) - dependent mechanism. With high-intensity exercise, increased extracellular osmolarity is accompanied by large increases in extracellular [lactate-]. We hypothesized that large increases in [lactate-] and osmolarity augment the NKCC-dependent RVI response observed with a NaCl (or sucrose) - induced increase in osmolarity alone; a response that is dependent on lactate- influx through monocarboxylate transporters (MCTs). Single mouse muscle fibres were isolated and visualized under light microscopy under varying osmolar conditions. When solution osmolarity was increased by adding NaLac by 30 or 60 mM, fibres lost significantly less volume and regained volume sooner compared to when NaCl was used. Phloretin (MCT1 inhibitor) accentuated the volume loss compared to both NaLac controls, supporting a role for MCT1 in the RVI response in the presence of elevated [lactate-]. Inhibition of MCT4 (with pCMBS) resulted in a volume loss, intermediate to that seen with phloretin and NaLac controls. Bumetanide (NKCC inhibitor), in combination with pCMBS, reduced the magnitude of volume loss, but volume recovery was complete. While combined phloretin-bumetanide also reduced the magnitude of the volume loss, it also largely abolished the cell volume recovery. In conclusion, RVI in skeletal muscle exposed to raised tonicity and [lactate-] is facilitated by inward flux of solute by NKCC- and MCT1-dependent mechanisms. This work demonstrates evidence of a RVI response in skeletal muscle that is facilitated by inward flux of solute by MCT-dependent mechanisms. These findings further expand our understanding of the capacities for skeletal muscle to volume regulate, particularly in instances of raised tonicity and lactate- concentrations, as occurs with high intensity exercise.
Highlights
High intensity exercise increases plasma and tissue extracellular osmolarity throughout the body due to simultaneous flux of solutepoor fluid into contracting muscles [1,2,3] and accumulation of lactate- in extracellular fluids [4]
This study demonstrates, for the first time, that both Na-K-2Cl co-transporter (NKCC) and MCT1 are involved in volume regulation by non-contracting skeletal muscle fibres; a set of findings that significantly improves our understanding of skeletal muscle volume regulation [25]
Raising extracellular osmolarity using sucrose or NaCl may have differing effects on the initial cell volume loss and subsequent regulatory volume increase (RVI) because of the differences in sarcolemmal permeability and conductance to sucrose compared to Cl
Summary
High intensity exercise increases plasma and tissue extracellular osmolarity throughout the body due to simultaneous flux of solutepoor fluid into contracting muscles [1,2,3] and accumulation of lactate- in extracellular fluids [4]. In response to volume loss (and resultant cell shrinkage), skeletal muscle fibres have recently been shown to exhibit a regulatory volume increase (RVI) that is mediated by a bumetanide- and ouabain-sensitive ion transport process [5]. Given that extracellular lactate- concentration ([lactate-]) is increased during exercise, and because lactate- is osmotically active, we hypothesized that elevated extracellular [lactate-] concomitant with increased extracellular osmolarity would augment the NKCC-dependent RVI (see Figure 1). In vivo, such an effect would mitigate the cell shrinkage that occurs in non-contracting muscle [1,2] during periods of exercise. In contrast to erythrocytes, where a chloride-bicarbonate exchanger (band 3 protein) accounts for 3–10% of net lactate- transport [9], this transporter does not appear to be present in skeletal muscle [8]
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