In the search for ways to slow the age-related loss of muscle mass that afflicts every older person, researchers here find that ATF5 is a point of control that regulates a trade-off between muscle mass and muscle quality. Mice lacking functional ATF5 retain muscle mass with age, but muscle quality declines to a greater degree instead. This rules it out as a target for therapy. It is always possible that further investigation of the interactions surrounding ATF5 will lead to insight into how to decouple mass versus quality, but that sort of investigation of biochemical pathways tends to take a very long time.
In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging.
To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body knockout (KO) and wild-type (WT) male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial reactive oxygen species production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of mitochondrial protease LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance.
Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.
