Skeletal muscle-specific Keap1 disruption modulates fatty acid utilization and enhances exercise capacity in female mice

Abstract

Skeletal muscle health is important for the prevention of various age-related diseases. The loss of skeletal muscle mass, which is known as sarcopenia, underlies physical disability, poor quality of life and chronic diseases in elderly people. The transcription factor NRF2 plays important roles in the regulation of the cellular defense against oxidative stress, as well as the metabolism and mitochondrial activity. To determine the contribution of skeletal muscle NRF2 to exercise capacity, we conducted skeletal muscle-specific inhibition of KEAP1, which is a negative regulator of NRF2, and examined the cell-autonomous and non-cell-autonomous effects of NRF2 pathway activation in skeletal muscles. We found that NRF2 activation in skeletal muscles increased slow oxidative muscle fiber type and improved exercise endurance capacity in female mice. We also observed that female mice with NRF2 pathway activation in their skeletal muscles exhibited enhanced exercise-induced mobilization and β-oxidation of fatty acids. These results indicate that NRF2 activation in skeletal muscles promotes communication with adipose tissues via humoral and/or neuronal signaling and facilitates the utilization of fatty acids as an energy source, resulting in increased mitochondrial activity and efficient energy production during exercise, which leads to improved exercise endurance.

The KEAP1-NRF2 System in Healthy Aging and Longevity

“…Similarly, one of the NRF2-inducing phytochemicals, curcumin, improves exercise performance in mice with heart failure [ 166 ]. Moreover, genetic activation of NRF2 in skeletal muscles increases the slow oxidative muscle fiber type and improves exercise endurance capacity in female mice [ 167 ].…”

Contribution of NRF2 to sulfur metabolism and mitochondrial activity

“…Recent studies have also clarified that appropriate activation of NRF2 has antiaging effects by limiting the accumulation of oxidative damage in tissues [ [8] , [9] , [10] ]. Moreover, NRF2 has been reported to confer resistance against mitochondrial toxins [ 11 , 12 ], protect against mitochondria-related disorders such as Parkinson's disease and Alzheimer's disease [ 13 , 14 ] and improve skeletal muscle performance and exercise endurance with increased oxygen consumption [ 15 , 16 ]. These reports suggest that NRF2 plays a crucial role in the regulation of mitochondrial function.…”

The Role of Nrf2 in Skeletal Muscle on Exercise Capacity

“…Another study demonstrated that improvement in aerobic capacity after forced treadmill running, which is observed in WT mice, is not observed in Nrf2 KO mice [ 36 ]. Recently, Keap1 deficiency, which activates the Nrf2 pathway, has been shown to enhance exercise capacity as well as force generation in mouse skeletal muscles [ 35 , 55 ]. Moreover, Sulforaphane treatment, which is known to activate Nrf2, increases running distance in an exhaustive treadmill running test in WT mice [ 53 ], and alleviates the reduction in grip strength and exercise capacity in mdx mice, the most widely used animal model of Duchenne muscular dystrophy [ 56 ].…”