Autophagy is the name given to a collection of processes responsible for recycling damaged, harmful, or unwanted proteins and structures in cells. In general autophagy declines with age and this is a problem, allowing long-lived cells to accumulate damage and dsyfunction. There is considerable focus in the research community on ways to enhance autophagy, based on evidence that upregulation of autophagy occurs as a beneficial response to stress, improving health and lengthening life. Calorie restriction is the most studied example of this response.
Nothing is simple and universal in biochemistry, however. In muscle tissue, autophagy instead increases with age, to the point at which it becomes harmful to cell and tissue function. This may be one of the contributions to sarcopenia in older individuals, the progressive loss of muscle mass and strength - though the size of the effect in comparison to the many other contributing factors can be debated. In today's open access paper, the authors report on their investigation of the proximate causes of this excessive autophagy. They point to a loss of Nrf2 expression, which may or may not be a useful target for potential interventions.
Autophagy is an evolutionary conserved housekeeping cellular degradation and recycling process, whereby misfolded proteins and exhausted organelles are degraded to maintain cellular homeostasis. Skeletal muscle is the most abundant tissue in human body, accounting for about 40-55% of the body weight. Autophagy plays a key role in the regulation of muscle mass, either excessive or impaired autophagy leads to muscle mass wasting. Deficiency in the basic autophagy function causes accumulation of misfolded proteins and exhausted organelles and results in skeletal muscle cell dysfunction and death. On the contrary, excessive autophagy can also be deleterious by causing cellular stress and muscle protein degradation.
Muscle mass declines with increasing age, which is termed sarcopenia. Several animal models have showed that ablation of autophagy function results in precocious aging and muscle wasting in mice. However, it is still controversial about the changes of autophagy function in skeletal muscle with increasing age. Based on the evidence from lower organisms and non-muscle tissue, most literature held the concept that skeletal muslcle autophagy declines with aging. On the contrary, a recent study showed that autophagy and mitophagy in mice muscle were enhanced during aging, which may contribute to the decline in organelle contents and muscle mass, but serve to maintain a healthy organelle pool and muscle cells function.
Inconsistent results in the literature suggested that the measurement of autophagy-related proteins at the static level can often lead to discrepancies in interpretation, because autophagy is a dynamic process. Therefore, measurement of autophagy flux is necessary to reflect the real condition of autophagy within muscle cells during aging. Until a recent study, no previous studies have investigated the alterations of autophagy during aging in skeletal muscle using autophagy flux measurement. In contrast with most previous studies, our study showed that increasing age lead to a trend of increased autophagy in skeletal muscle, using autophagy flux measurements.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a cytoprotective gene which mainly functions to protect cells against oxidative stress and toxicants. In recent years, increasing evidence has revealed the role of Nrf2 in the regulation of autophagy. Our study showed that Nrf2 knockout decreased the levels of autophagy-related proteins, which was in consistent with previous studies. However, the explanation of our results was different from previous studies. Using autophagy flux measurements, we proved that Nrf2 knockout significantly increased autophagy in the muscle tissue. Therefore, we attributed the decreased levels of autophagy-related proteins in the Nrf2 knockout mice to the faster clearance of these proteins by autophagy.
Several previous studies have investigated the effect of aging on the expression of Nrf2 and its downstream cytoprotective genes in the skeletal muscle but the results were inconsistent. In recent years, increasing studies have recognized that expression of Nrf2 and its downstream genes in the skeletal muscle can be activated by physical exercise. Elderly humans who have a physically active lifestyle have an even higher expression level of Nrf2 and its downstream cytoprotective proteins compared with young subjects. This can partially explain the inconsistent previous studies regarding the effect of aging on the expression of Nrf2 and its downstream cytoprotective genes.
In conclusion, our study demonstrated that Nrf2 deficiency promoted the increasing trend of autophagy during aging in skeletal muscle. Nrf2 deficiency and increasing age may cause excessive autophagy in skeletal muscle, which can be a potential mechanism for the development of sarcopenia.