Autophagy Impairment in Muscle Induces Neuromuscular Junction Degeneration and Precocious Aging

The cellular basis of age-related tissue deterioration remains largely obscure. The ability to activate compensatory mechanisms in response to environmental stress is an important factor for survival and maintenance of cellular functions. Autophagy is activated both under short and prolonged stress and is required to clear the cell of dysfunctional organelles and altered proteins. We report that specific autophagy inhibition in muscle has a major impact on neuromuscular synaptic function and, consequently, on muscle strength, ultimately affecting the lifespan of animals. Inhibition of autophagy also exacerbates aging phenotypes in muscle, such as mitochondrial dysfunction, oxidative stress, and profound weakness. Mitochondrial dysfunction and oxidative stress directly affect acto-myosin interaction and force generation but show a limited effect on stability of neuromuscular synapses. These results demonstrate that age-related deterioration of synaptic structure and function is exacerbated by defective autophagy. [Display omitted] •Autophagy in muscle decreases with age, and rescue prevents muscle loss•Autophagy inhibition in muscles shortens animal lifespan•Autophagy is required to maintain a normal muscle-nerve interaction•Autophagy impairment induces oxidation of contractile proteins, causing weakness The cellular basis of age-related tissue deterioration remains largely obscure. Autophagy is often activated under stress conditions and declines with age. Carnio et al. now report that specific autophagy inhibition in muscle has a major impact on neuromuscular synaptic function and consequently on muscle strength, ultimately affecting the lifespan of animals. Autophagy inhibition also exacerbates several aging phenotypes, confirming that autophagy is required for healthy aging.