Abstract
Muscle atrophy caused by disuse is accompanied by adverse physiological and functional consequences. Satellite cells are the primary source of skeletal muscle regeneration. Satellite cell dysfunction, as a result of impaired proliferative potential and/or increased apoptosis, is thought to be one of the causes contributing to the decreased muscle regeneration capacity in atrophy. We have previously shown that electrical stimulation improved satellite cell dysfunction. Here we test whether electrical stimulation can also enhance satellite cell proliferative potential as well as suppress apoptotic cell death in disuse-induced muscle atrophy. Eight-week-old male BALB/c mice were subjected to a 14-day hindlimb unloading procedure. During that period, one limb (HU-ES) received electrical stimulation (frequency: 20 Hz; duration: 3 h, twice daily) while the contralateral limb served as control (HU). Immunohistochemistry and western blotting techniques were used to characterize specific proteins in cell proliferation and apoptosis. The HU-ES soleus muscles showed significant improvement in muscle mass, cross-sectional area, and peak tetanic force relative to the HU limb (p<0.05). The satellite cell proliferative activity as detected within the BrdU+/Pax7+ population was significantly higher (p<0.05). The apoptotic myonuclei (detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) and the apoptotic satellite cells (detected by cleaved Poly [ADP-ribose] polymerase co-labeled with Pax7) were reduced (p<0.05) in the HU-ES limb. Furthermore the apoptosis-inducing factor and cleaved caspase-3 were down-regulated while the anti-apoptotic Bcl-2 protein was up-regulated (p<0.05), in the HU-ES limb. These findings suggest that the electrical stimulation paradigm provides an effective stimulus to rescue the loss of myonuclei and satellite cells in disuse muscle atrophy, thus maintaining a viable satellite cell pool for subsequent muscle regeneration. Optimization of stimulation parameters may enhance the outcome of the intervention.
Highlights
Skeletal muscles are highly adaptive for functional changes and external insults
A significant difference was observed in the fiber cross-sectional area between the hindlimb was subjected to electrical stimulation (HU-ES) and HU groups in which electrical stimulation partially attenuated the unloading-induced reduction in the fiber cross-sectional area (HUES: 1481.55 6 121.44 mm2; p,0.05)
Mechanical unloading is associated with detrimental changes to the structure and function of skeletal muscles, characterized by reduction in muscle mass, myofiber cross-sectional area, contractile strength and speed, as well as slow-to-fast fiber type transformation
Summary
Skeletal muscles are highly adaptive for functional changes and external insults. Adult skeletal muscle fibers are terminally differentiated tissues, such that regeneration of skeletal muscle from injury depends on recruitment of resident satellite cells. Mechanical unloading has been shown to reduce the numbers of satellite cells, probably due to impaired satellite cell proliferation, resulting in decreased muscle mass and protein content [6,7,8]. In addition to the reduced numbers of satellite cells, satellite cells isolated from the unloaded muscles failed to proliferate and differentiate into multinucleated myotubes [9]. These results further confirmed that mechanical unloading impaired both the numbers as well as the regenerative capacity of satellite cells. Whether physical, chemical, or biological, that enhances the satellite cell proliferation and/or inhibition of apoptosis (myonuclei or satellite cells), should be efficient in rescuing skeletal muscle atrophy
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