Attenuation of autophagy impacts on muscle fibre development, starvation induced stress and fibre regeneration following acute injury.

Abstract

Autophagy has been implicated as a major factor in the development of a number of diseases of skeletal muscle. However, its role in skeletal muscle homeostasis is still evolving. We examined skeletal muscle architecture in a mouse model, Atg16L1, where autophagy is attenuated but importantly still present. We show that muscle fibres from Atg16L1 mice were smaller than wild-type counterparts, proving a role for this process in the growth of these cells. We show that mild attenuation of autophagy results in accelerated muscle loss during the initial phase of acute starvation. Furthermore, we show that regeneration of skeletal muscle following cardiotoxin (CTX) mediated injury is slower in the Atg16L1 mouse compared to wild-type. Lastly, we show that autophagy controls the integrity of the sarcolemma. Attenuated autophagy makes muscle fibres more susceptible to infiltration by circulating immunoglobulins following muscle injury with CTX. These fibres internalise dystrophin and nNOS. Importantly these fibres are able to restore dystrophin and nNOS localisation and do not die. In conclusion, these studies shed new light into the ability of skeletal muscle fibres to cope with injury and establish a link between the fine-tuning of autophagy and skeletal muscle regeneration.