| Skeletal muscle disuse atrophy occurs during prolonged periods of reduced muscle activity often seen with bed rest, limb immobilization, and space flight. Muscle injury or lack of mechanical activity causes disruptive nitric oxide synthase (NOS) activity, which is sufficient to induce forkhead box O-3a, muscle RING finger-1, and muscle atrophy F-box, and nuclear factor-kappa B (NF-kappaB) through classical and alternative pathways, respectively. Paradoxically, increased nitric oxide production is caused by muscle loading and is essential for muscle growth. This is the first study to develop two completely intrinsic models of skeletal muscle atrophy in vitro: (1) withdrawal from moderate cyclic stretch, and (2) high magnitude cyclic strain. First, moderate cyclic mechanical stretch can be used as a model of activity in cultured skeletal muscle myotubes, and increased myotube size through NOS-dependent Akt signaling. Cessation of moderate stretch caused protein degradation, altered neuronal NOS localization, and a reduction in myotube size via downregulation of Akt, which may contribute to NF-kappaB signaling through an alternative pathway. Secondly, high magnitude cyclic strain induced the classical pathway of NF-kappaB signaling and upregulated inducible NOS. These data demonstrated in vitro models of atrophy independent of external factors and provide evidence to better understand the signaling pathways involved during skeletal muscle loss. |
