Uniaxial Cyclic Stretch-Stimulated Glucose Transport Is Mediated by a Ca²⁺-Dependent Mechanism in Cultured Skeletal Muscle Cells

Abstract

Objective: Mechanical stimuli such as stretch increase glucose transport and glycogen metabolism in skeletal muscle. However, the molecular mechanisms involved in the mechanotransduction events are poorly understood. The present study was conducted in order to determine whether the signaling mechanism leading to mechanical stretch-stimulated glucose transport is similar to, or distinct from, the signaling mechanisms leading to insulin- and contraction-stimulated glucose transport in cultured muscle cells. Methods: Cultured C2C12 myotubes were stretched, after which the 2-deoxy-D-glucose (2-DG) uptake was measured. Results: Following cyclic stretch, C2C12 myotubes showed a significant increase in 2-DG uptake, and this effect was not prevented by inhibiting phosphatidylinositol 3-kinase or 5′-AMP-activated protein kinase and by extracellular Ca²⁺ chelation. Conversely, the stretch-stimulated 2-DG uptake was completely prevented by dantrolene (an inhibitor of Ca²⁺ release from sarcoplasmic reticulum). Furthermore, the stretch-stimulated 2-DG uptake was prevented by the Ca²⁺/calmodulin-dependent kinase inhibitor KN93 which did not prevent the insulin-stimulated 2-DG uptake. Conclusions: These results suggest that the effects of stretch-stimulated glucose transport are independent of the insulin-signaling pathway. By contrast, following mechanical stretch in skeletal muscle, the signal transduction pathway leading to glucose transport may require the participation of cytosolic Ca²⁺ and Ca²⁺/calmodulin kinase, but not 5′-AMP-activated protein kinase.

Effect of self‐administered stretching on NIRS‐measured oxygenation dynamics

“…As such, this adaptive phase allows for a more coordinated distribution of blood flow to deliver more blood flow to metabolically active sites. Furthermore, it has also been shown that skeletal muscle hypoxia (reduced O 2 ) and/or passive stretch can increase glucose transport and translocation of glucose transporters (Cartee et al ., ; Iwata et al ., ). Additional evidence reveals that following exercise, elevations in glucose uptake and glycogen repletion follow a similar time course as that of skeletal muscle blood flow (Ivy, ).…”

Cyclic stretch reduces myofibrillar protein synthesis despite increases in FAK and anabolic signalling in L6 cells

“…Recent work by Rose and colleagues clarified this mechanism by demonstrating that the suppression of protein synthesis by contraction was partially dependent upon Ca 2+ ‐dependent activation of eEF2K (Rose et al 2009). However, Ca 2+ influx is not specific to contraction: stretch‐induced 2‐deoxyglucose uptake in C2C12 myotubes is prevented by the ryanodine receptor 1 (RyR1) inhibitor dantrolene and stretch of myotubes increases Ca 2+ influx via mechanically sensitive plasma membrane ion channels suggesting that both sarcoplasmic reticulum and extracellular derived Ca 2+ are increased with stretch (Nakamura et al 2001; Iwata et al 2007). Therefore we wondered if stretch‐induced Ca 2+ currents could induce eEF2K activity and thereby stimulate inhibitory phosphorylation of eEF2.…”

Biophysical cues enhance myogenesis of human adipose derived stem/stromal cells

“…For example, application of cyclic strain to primary human myoblasts enhanced elasticity, myofiber diameter and area when compared to static culture conditions [25]. Similarly, enhanced metabolic activity of C2C12 mouse myoblasts were observed in response to 10% cyclic stretch [31] and, conversely, cessation of 12% stretch on C2C12 cultures caused myotube atrophy [32]. Thus, we hypothesized that biophysical cues (cyclic uniaxial strain) in conjunction with biochemical stimuli (azacytidine) would induce ASCs to exhibit enhanced myogenic outcomes (alignment, multi-nucleation, and expression of muscle-specific proteins) and significantly improve the efficiency of differentiation.…”