Rejuvenation of aged neuromuscular junctions (NMJ) by exposure to a young systemic environment

Age-related loss of muscle mass and function, also known as sarcopenia, is a significant problem that has serious implications for quality of life in the elderly. Although the precise mechanism of sarcopenia is not completely understood, several lines of evidence suggest that the functional decline in skeletal muscle stem cells and inability to repair after injury, contribute directly to age-associated deterioration of skeletal muscle. Our data using heterochronic parabiosis and stem cell transplantation models suggests that the circulatory system serves as an important source of such signals. In particular, exposure of aged muscle, to a “youthful” systemic environment appears to reverse many indicators of age-related pathology and restores robust muscle regeneration after injury. Our ongoing analyses of the molecules responsible for these effects point to discrete metabolic and hormonal mediators as key effectors of this systemic rejuvenating response. Systemic regulators also appear to influence age-related changes in the integrity of neuromuscular junctions and presynaptic motor neurons, either directly or through perturbation of myofiber stability and repair. Interestingly, we have found significant differences in the impact of denervation on muscle stem cell function in a mouse model based on muscle stem cell transplantation, suggesting an age-dependent influence of motor neuron damage/degeneration on muscle repair potential. Taken together, these data point to complex regulatory interactions within the muscle stem cell niche in determining muscle repair potential in aged individuals, and suggest that targeting these interactions could provide new avenues to reverse age-dependent loss of muscle function and accelerate recovery after muscle injury.