The role of Piezo1 in skeletal muscle adaptation
Summary
Mechanical stimuli such as that generated by exercise promote muscle generation and function. In contrast, loss of physical activity results in muscle atrophy. Mitochondria are essential for energy production and cellular function in skeletal muscle cells. Exercise training is well known to promote mitochondrial biogenesis and enhance mitochondrial function in skeletal muscle, leading to improvements in whole-body metabolic homeostasis, exercise performance, and fatigue resistance. Disuse, on the other hand, decreases mitochondrial function. Importantly, conditions with impaired mitochondrial function, such as aging and obesity, are often associated with reduced responsiveness to exercise. Agents that enhance mitochondrial function such as Resveratrol have been shown to improve exercise induced muscle adaptation in obese populations. Thus, mitochondrial function appears to play an important role in skeletal muscle adaptation. However, the molecular mechanisms underlying are unclear.
Piezo1, a mechanosensitive ion channel, has emerged as a critical mechanosensor responding to various forms of mechanical stimulation including stretch and fluid shear stress. In vitro, activation of Piezo1 using Yoda1, a Piezo1 agonist, mimics mechanical stimulation in various cell types including endothelial and bone cells. In vivo, Piezo1 plays critical roles in maintaining bone homeostasis and mechanical load induced bone formation. In preliminary studies, we found that Piezo1 deletion reduces expression of mitochondria-related genes, oxygen consumption rate, and ATP production. Moreover, activation of Piezo1 by Yoda1 increased mitochondrial biogenesis and energy production in bone cells. These increases were abolished in Piezo1 knockout cells, indicating that Piezo1 is required for agonist-enhanced mitochondrial function. Therefore, we propose that mechanical stimulation promotes mitochondrial function through Piezo1 and activation of Piezo1 could attenuate skeletal muscle loss caused by disuse.
Specific Aim 1: Determine whether Piezo1 is essential for mechanical stimulation induced mitochondrial biogenesis and function in myocytes. To do this, we will generate Piezo1 knock-down C2C12 cells, a mouse skeletal muscle cell line. Fluid shear stress will be used since evidence suggest that mechanically loaded muscles in vivo experience not only tensile strain but also shear stress. Cells under fluid shear stress will be harvested for mitochondrial staining, measurements of mitochondrial DNA content, and citrate synthase activity to evaluate mitochondrial biogenesis. ATP production will also be measured in these cells to determine mitochondrial function.
Specific Aim 2: Determine whether activation of Piezo1 promotes skeletal muscle cell mitochondrial biogenesis and function. To accomplish this, we will treat C2C12 cells with Yoda1. Mitochondria biogenesis and function will be evaluated in these cells.
Specific Aim 3: Determine whether activation of Piezo1 alleviates muscle atrophy induced by tail suspension. C57BL/6 mice will be tail suspended for a 4-week period. Yoda1 will be administrated daily during suspension. Body composition of these mice will be assessed by dual-energy x-ray absorptiometry. Grip strength of the hind-limb will be determined in the beginning and the end of the experiment. Skeletal muscles will be collected for muscle mass measurements, gene expression, and histology analysis.
These studies will provide new strategies to modulate muscle regeneration and for development of new approaches to ameliorate muscle loss associated with immobilization and aging.
Keywords:
- Muscle adaptation
- Mechanotransduction
- Mitochondria
- Calcium channel
Researchers:
- Jinhu Xiong (Author)
- Nicholas Greene
- Zufeng Ding
- Xuehua Li