Accelerated sarcopenia in Cu/Zn superoxide dismutase knockout mice

Abstract

Mice lacking Cu/Zn-superoxide dismutase (Sod1^-/- or Sod1KO mice) show high levels of oxidative stress/damage and a 30% decrease in lifespan. The Sod1KO mice also show many phenotypes of accelerated aging with the loss of muscle mass and function being one of the most prominent aging phenotypes. Using various genetic models targeting the expression of Cu/Zn-superoxide dismutase to specific tissues, we evaluated the role of motor neurons and skeletal muscle in the accelerated loss of muscle mass and function in Sod1KO mice. Our data are consistent with the sarcopenia in Sod1KO mice arising through a two-hit mechanism involving both motor neurons and skeletal muscle. Sarcopenia is initiated in motor neurons leading to a disruption of neuromuscular junctions that results in mitochondrial dysfunction and increased generation of reactive oxygen species (ROS) in skeletal muscle. The mitochondrial ROS generated in muscle feedback on the neuromuscular junctions propagating more disruption of neuromuscular junctions and more ROS production by muscle resulting in a vicious cycle that eventually leads to disaggregation of neuromuscular junctions, denervation, and loss of muscle fibers.

Fig. 1.. Comparison of muscle atrophy in WT and Sod1KO mice as they age.

The mass of the gastrocnemius is shown relative to the lifespan of WT (blue) and Sod1KO (red) mice. The figure represents a composite of data from Muller et al. [10], Jang et al. [4]; and Larkin et al. [7].

Fig. 2.. Neuromuscular junction degeneration in WT and Sod1 KO mice.

The photographs show the NMJ immunofluorescence for gastrocnemius of 8- and 30-month-old WT mice and 18-month-old Sod1KO mice. The graph shows the percent of NMJs that are normal (blue bars) and fragmented (red bars). Data are taken from Larkin et al. [7] and Jang et al. [5,6].

Fig. 3.. ROS generation by muscle mitochondria in three models of sarcopenia.

The generation of hydrogen peroxide by isolated mitochondria from the gastrocnemius is show for young and old mice, Sod1KO mice (20 month old) and ALS mice, (G93A). These data are taken from Muller et al. [10,11], and the * indicates those values that are significantly different from the WT controls.

Fig. 4.. Effect of genetic manipulations on the mass and function of muscle.

The mass (blue) and function (maximum isometric specific force, gold) for gastrocnemius is shown at 8–10 months of age for four genetic mouse models compared to WT mice. The * indicates those values that are significantly different than WT mice. Data are taken from Larkin et al. [7] for Sod1KO mice; Sakellariou et al. [13] for nTg/Sod1KO mice; Zhang et al. [19] for mSod1KO mice, and Sataranataranjan et al. [16] for nSod1 KO mice.

Fig. 5.. Proposed two-hit model describing the molecular mechanism leading to loss of muscle mass and function in Sod1KO mice.

The oxidized redox state in motor neurons initiates disruption of NMJs leading to mitochondrial dysfunction and increased ROS production. The mtROS generated in muscle feeds-back on the NMJs propagating more NMJ dysfunction and more mtROS production resulting in a vicious cycle that eventually leads to NMJ disaggregation, denervation, and loss of muscle fibers.