NOX4 in the Age-Related Decline of Muscle Adaptation to Exercise
Loss of muscle mass and strength with age is universal, leading both to physical frailty and to a harmful disruption of metabolism more generally. Muscle doesn't just exist to provide motive power, it is also a metabolically active tissue. The signals it provides are important to insulin metabolism, for example, in addition to the systemic benefits that result from exercise. The causes of age-related muscle decline are complex and layered. For example, low-level molecular damage of the sort described in the Strategies for Engineered Negligible Senescence (SENS) and the Hallmarks of Aging disrupt the function of neuromuscular junctions linking the nervous system to muscle fibers, and those nerve signals are necessary for the normal adaptive response of muscle tissue. But completely separately, muscle stem cells become progressively less active with age, and the somatic muscle cells produced by those stem cells are needed for muscle growth and regeneration.
All of this is attended by altered levels of expression of countless genes, some of which are more important than others when it comes to regulating the behavior of muscle cells. In today's open access paper, for example, researchers discuss the role of NOX4 in muscle adaptation to use. In youth, using muscle will grow muscle. In later life this becomes less the case. NOX4 appears to occupy an important position in the regulation of this response to exercise, and its levels decline with age. Energetic use of muscle generates oxidative stress through increased activity of mitochondria, and this increase in the production of oxidative molecules as a side-effect of energy metabolism is the primary signal triggering a cascade of protective and adaptive responses. NOX4 is necessary to that process as a producer of specific forms of oxidative molecule; having less of it doesn't just prevent muscle growth, but paradoxically increases the harms done by oxidative signaling as the protective response is attenuated.
Adaptations to stressors can increase resilience and allow organisms to manage damaging insults. The ability of organisms to transiently adapt to otherwise harmful stressors is known as adaptive homeostasis. A quintessential example of adaptive homeostasis is the response to oxidants, namely, reactive oxygen species (ROS). ROS are highly reactive chemicals generated in response to stressors and as byproducts of life in an aerobic environment. While evolution has harnessed specific ROS, for example, H2O2 for physiological roles such as cellular signaling, stressors resulting in redox imbalance and excess ROS can damage essential macromolecules including proteins, lipids, and DNA to promote cell death and inflammation and contribute to disease.
A decline in both nuclear factor erythroid 2-related factor 2 (NFE2L2)-orchestrated adaptive homeostasis and consequently greater oxidative distress are thought to be key features of aging. In contracting skeletal muscle, the reactive oxygen species-producing enzyme NADPH oxidase 4 (NOX4) is a potent inducer of NFE2L2 adaptive homeostasis. Here, we report that skeletal muscle NOX4 levels decline in aged mice and humans, resulting in abrogated NFE2L2 adaptive homeostasis, increased protein oxidative damage, and decreased muscle function.
We show that deleting NOX4 in skeletal muscle exacerbates the physiological decline associated with aging, resulting in overt sarcopenia and frailty, characterized by physical inactivity, increased adiposity, systemic inflammation, whole-body insulin resistance, and advanced liver disease in aged chow-fed mice. The systems-wide physiological decline in aged skeletal muscle NOX4-deficient mice could be corrected by restoring NOX4 using viral approaches or activating NFE2L2 downstream with sulforaphane and reinstating adaptive homeostatic responses otherwise induced by exercise. Our findings provide important insights into the basis for the decline in NFE2L2-orchestrated adaptive homeostasis that accompanies physical inactivity with age and identify key mechanisms by which exercise may promote healthy aging.