Activation of autophagy is required for muscle homeostasis during physical exercise

Abstract

Skeletal muscle fibers of collagen VI null (Col6a1−/−) mice show signs of degeneration due to a block in autophagy, leading to the accumulation of damaged mitochondria and excessive apoptosis. Attempts to induce autophagic flux by subjecting these mutant mice to long-term or shorter bursts of physical activity are unsuccessful (see Grumati, et al., pp. 1415–23). In normal mice, the induction of autophagy in the skeletal muscles post-exercise is able to prevent the accumulation of damaged organelles and maintain cellular homeostasis. Thus, these studies provide an important connection between autophagy and exercise physiology.

Keywords: :

• lysosome
• metabolism
• physiology
• stress
• vacuole

The skeletal muscle is the most abundant tissue in mammals and also the main amino acid warehouse in the body; accordingly, its physiological state plays a very important role in health.¹ Optimal autophagic flux is required for the maintenance of the integrity of skeletal fibers, which are the basic contractile units of skeletal muscles. Both excess and reduced levels of autophagy are detrimental for muscle health; the former results in the loss of muscle mass, whereas the latter causes skeletal fiber degeneration and weakness.² Muscular atrophy observed in mice with muscle-specific knockout of the autophagy genes Atg5 or Atg7 reinforces the role of autophagy in skeletal muscle homeostasis.^3,4

Mutations in any of the three genes that encode collagen VI, one of the major skeletal muscle extracellular matrix proteins, result in Bethlem myopathy and Ullrich congenital muscular dystrophy (UMCD) in humans.⁵ Collagen VI-deficient (Col6a1^−/−) mice, the animal model of these diseases, are characterized by decreased muscle strength, skeletal muscle degeneration and a high rate of apoptosis. An investigation of the mechanism leading to these phenotypes in Col6a1^−/− mice revealed impaired activation of the autophagic machinery resulting in an accumulation of defective organelles such as dilated sarcoplasmic reticulum and swollen mitochondria that may result in apoptosis and, ultimately, muscle wasting.⁶

In a previous paper, Grumati et al. determined that as a result of malfunctioning autophagy, Col6a1^−/− mice accumulate defective mitochondria in the diaphragm and tibialis anterior muscles.⁶ Specifically, these mitochondria have a latent dysfunction when compared with their wild-type counterparts, resulting in defective mitochondrial membrane potential, accumulation of reactive oxygen species, myofiber damage⁷ and activation of apoptosis.⁸ Interestingly, in Col6a1^−/− mice, the induction of autophagy by different means such as longer starvation periods, maintenance on a low protein diet, or treatment with the autophagy inducer rapamycin, clears the accumulation of defective mitochondria and dilated sarcoplasmic reticulum and reduces the number of apoptotic nuclei. The levels of BECN1, a protein required for autophagosome biogenesis, are low in Col6a1^−/− mice and in patients with Bethlem myopathy and UMCD. Furthermore, the transfection of a plasmid to increase expression of BECN1 in the tibialis anterior muscle activates normal autophagy and suppresses apoptosis in myofibers of Col6a1^−/− mice. These results underscore the potential benefits of reactivating normal levels of autophagy in the treatment of some muscular pathologies.

Physical exercise promotes mitochondrial biogenesis and improves mitochondrial function, and most of the beneficial effects of physical exercise are mediated by the action of the transcriptional coactivator PGC-1α that prevents muscle loss during dieting, disease states such as chronic cardiac failure and aging.⁹ Accordingly, the authors hypothesize that exercise might improve mitochondrial function by triggering autophagy in Col6a1-deficient mice. The notion that the reactivation of autophagy via physical exercise may ameliorate muscle myopathy is particularly relevant in the treatment and management of skeletal muscle-related diseases. In contrast to their original hypothesis, the authors found that while physical activity stimulates autophagy in normal muscles, neither long-term nor shorter spurts of intense physical activity stimulate autophagy in Col6a1^−/− mice. Both the tibialis anterior and diaphragm muscles of these, but not wild-type, mice show severe signs of myofiber death and degeneration, mitochondrial abnormalities and elevated levels of apoptosis. Furthermore, the autophagic flux in both muscles is significantly reduced after either kind of physical activity in Col6a1^−/− mice, and there is a concomitant increase in phospho-Akt levels. Muscles from Col6a1^−/− mice expressing GFP-LC3 show very few autophagosomes (GFP-LC3 puncta) after 1 h of exercise on a treadmill compared with the wild-type mice. Overall, the results concerning a connection between physical exercise and the mitigation of disease symptoms and cell death via the induction of autophagy in Col6a1^−/− mice may seem discouraging with regard to therapeutic potential. Nonetheless, the study clearly shows that the activation of autophagy during physical activity in muscle cells is necessary for maintaining tissue homeostasis by preventing the accumulation of damaged mitochondria and myofibril degeneration.