The aged niche disrupts muscle stem cell quiescence

SUMMARY The niche is a conserved regulator of stem cell quiescence and function. During aging, stem cell function declines. To what extent and by which means age-related changes within the niche contribute to this phenomenon are unknown. We demonstrate that the aged muscle stem cell niche, the muscle fiber, expresses FGF2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose self-renewing capacity. We show that relatively dormant aged satellite cells robustly express Sprouty1 (spry1), an inhibitor of FGF signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing spry1, results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of FGFR1 signalling or overexpression of spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function

Neuromuscular synaptic patterning requires the function of skeletal muscle dihydropyridine receptors

Developing skeletal myofibers in vertebrates are intrinsically “pre-patterned” for motor nerve innervation. However, the intrinsic factors that regulate muscle pre-patterning remain unknown. Here we show that a functional skeletal muscle dihydropyridine receptor (DHPR, the L-type Ca(2+) channel in muscle) is required for muscle pre-patterning during the development of the neuromuscular junction (NMJ). Targeted deletion of the β1 subunit of DHPR (Cacnb1) in mice leads to muscle pre-patterning defects, aberrant innervation and precocious maturation of the NMJ. Reintroducing the Cacnb1 gene into Cacnb1(−/−) muscles reverses the pre-patterning defects and restores normal development of the NMJ. The mechanism by which DHPRs govern muscle pre-patterning is independent of their role in excitation-contraction coupling (E-C coupling), but requires Ca(2+) influx through the L-type Ca(2+) channel. Our findings demonstrate that the skeletal muscle DHPR retrogradely regulates the patterning and formation of the NMJ