I’m sure everyone experienced small or not so small forms of muscle soreness after a fitness session - a result of small damages in the muscle fibers. The regeneration of damaged fibres requires the presence of so-called satellite cells, which are muscle stem cells in a dormant state, meaning that they can re-enter the cell cycle to form new fibres upon activation. During ageing the number and functionality of satellite cells declines and thus lowers the regenerative potential of muscles, a process known as sarcopenia which inescapable hits all of us. A recent study in Nature this week identified autophagy or the process of degradation of long-lived proteins and damaged cell structures as correlated to the decline of satellite cell potential. The study prominently hints on a potential use in regenerative medicine: Re-installing autophagy in geriatric stages could (at least partially) restore the ability to fix small fibre damages and slow down the age-induced loss of muscle mass.

García-Prat et. al. investigated the activity of autophagy in young and old satellite cells using a GFP fused to LC3, a known marker of autophagosomes. Autophagosomes are required to deliver cellular waste to the lysosomes, an organelle were damaged cell parts or proteins are finally dismounted. Although GFP-LC3 signals were increased in old cells (confirming the presence of autophagosomes) the activity of autophagy was impaired, as shown by bafilomycin treatment to inhibit the flux of autophagosomes to lysosomes. Interestingly, treating cells from old mice with rapamycin, an autophagy-inducing drug, restored autophagy and reduced detection of stalled autophagosomes.

To investigate the impact of autophagy on stemcellness, the authors focused on Atg7, a protein crucial for autophagosome formation and Pax7, a marker for quiescent satellite cells. They crossed Atg7-floxed mice with Pax7-cre. This flox-cre construct will remove Atg7 if Pax7 is expressed in the cell. As expected, satellite cells lacked autophagosomes and, more importantly, there where less satellite cells present in the crossed animals. Since the remaining stem cells could not undergo differentiation (which is required for muscle regeneration), the loss of autophagy could be the cause for the age-associated numerical decline in muscle stem cells.

When talking about ageing, reactive-oxygen species (ROS) are not far away. Being also the case for satellite cells, García-Prat et. al. found higher ROS labelling and defective mitochondria in Atg7-deficient cells, as well as in young cells with blocked autophagy via Bafilomycin. Inhibiting ROS with a vitamin E analogue attenuated the autophagic block present in old cells and prevented the appearance of age-related markers and regenerative defects of satellite cells. As a result, the authors linked impaired autophagy and increased ROS levels to ageing in satellite cells.

As a working model, García-Prat et. al. describe the high level of autophagy flux in quiescent stem cells as a mechanism of proteotoxicity attenuation. Failure of autophagy results in increased levels of damaged proteins and organelles, generating enhanced ROS levels that trap the cell in a senescent state. It seems that cell populations with a low turnover, like quiescent stem cells, rely on autophagy to preserve their regenerative capacity - a fact that can be exploited pharmacologically by restoring autophagy or neutralize ROS in ageing cells.

Laura García-Prat, Marta Martínez-Vicente, Eusebio Perdiguero, Laura Ortet, Javier Rodríguez-Ubreva, Elena Rebollo, Vanessa Ruiz-Bonilla, Susana Gutarra, Esteban Ballestar, Antonio L. Serrano, Marco Sandri and Pura Muñoz-Cánoves. Autophagy maintains stemness by preventing senescence. Nature (2016), doi: 10.1038/nature16187 weblink

Cover Art: Claudia Bentley, http://www.nature.com/nature/outlook/ageing/