A new study conducted by researchers at the University of Sao Paulo in Brazil in partnership with colleagues in the U.S. and Norway and published in Scientific Reports, has shown that lack of muscle stimulus results in a buildup of inadequately processed proteins in muscle cells which in turn leads to muscle wasting and weakness. This typical muscle dysfunction is a condition commonly effecting the elderly, individuals who sit for long periods of time without any exercise and bedridden patients.

Test results from rats with induced sciatic nerve injury which stopped receiving stimuli, showed the protein buildup was caused by impairment of autophagy which is the cellular machinery responsible for identifying then removing damaged toxins and proteins. The analysis of the tests on the rats subjected to a regime of aerobic exercise training which were previous to injury enabled the researchers to demonstrate that physical exercise can keep the autophagic system primed and then facilitate its activity as necessary. This is similar to muscle dysfunction due to the lack of stimulus.

Daily exercise will sensitize the autophagic system which facilitates the elimination of organelles (any of a variety of organized or specialized structures within a living cell) and proteins that are not functional in the muscles. It is important that removal of these dysfunctional components occur. When they accumulate they will become toxic and contribute to muscle cell impairment and death.

A good example of what muscle autophagy is, is by comparing muscles working in a similar manner as a refrigerator which runs on electricity. If the signal ceases due to someone pulling the plug on the frig or in the case of muscles blocks the neurons that innervate the muscles, it won’t take too long for food in a frig to spoil and proteins in muscles to spoil at different rates according to their composition. At this point an early warning mechanism in cells activates the autophagic system which will identify, isolate and then incinerate the defective material which prevents propagation of the damage. If the muscles do not receive the right electric signals for long periods of time, the early warning mechanism will stop working properly and cell collapse will occur. Without autophagy, a cascade effect will occur which leads to cell death.

In the current study, rats were submitted to sciatic nerve ligation surgery which created an effect equal to that of sciatic nerve compression in humans. The pain this injury can cause prevents people from using the leg affected by the injury which will lead to weakened muscles and eventually atrophy of those muscles.

Previous to surgery, the rats were divided into two groups. One group remained sedentary while the other group was given exercise training which consisted of running at 60% maximum aerobic capacity for one hour a day, five days per week. After four weeks of exercise training, surgery was performed. The muscular dysfunction induced by sciatic nerve injury was discovered to be less aggressive in the group which had aerobic exercise than the group of rats that were sedentary. Biochemical and functional parameters in the affected muscles were also evaluated. The aerobic training increased autophagic flux and therefore reduced dysfunctional protein levels in the muscles of the rats. Occurring at the same time was improvement in the muscle tissue’s contractility properties. Exercise is a transient stress which will leave memory in the organism and in this case via the autophagic system. When the organism is subjected to a variety of stress, it is better prepared to respond and combat the effects.

The team performed two other experiments which were designed to more thoroughly investigate the link between autophagy and exercise. One experiment involved mice in which the autophagy related gene ATG7 was silenced in the skeletal system. ATG7 encodes a particular protein responsible for synthesizing a vesicle called the autophagosome which forms around dysfunctional organelles and then transports them to the lysosome where they are broken down and then digested. This particular experiment validated the importance of autophagy in muscle biology. ATG7 will knockout mice that had not been subjected to sciatic nerve litigation although displayed muscular dysfunction.

In the second experiment, muscles from rats with sciatic nerve injury and control rats without injury were treated with chloroquine, a drug which inhibits autophagy by raising the lysosomal pH or alkalinity and therefore prevents the degradation of defective proteins. These tests showed less muscle strength in the control group of rats treated with the drug than in the untreated group. Chloroquine had no effect at all on the muscles of the rats with the sciatic nerve injury showing that the inhibition of autophagy is critical to muscular dysfunction caused by lack of stimulus.

Rather than aiming to find a treatment for people who are unable to exercise adequately, the goal of the studies was to use an experimental model for future research to help understand the cellular processes involved in muscle dysfunction. This will help facilitate the development of interventions capable of minimizing or even reversing an increasingly serious problem with muscle weakness and atrophy caused by lack of movement. By identifying a molecule that will selectively keep the autophagic system alert similar to what happens during physical exercise, treatments may be developed which can be given to people with this type of muscle disorder which includes people who are bedridden for extended periods of time, patients with degenerative muscular diseases and the elderly.

To view the original scientific study click here: Exercise prevents impaired autophagy and proteostasis in a model of neurogenic myopathy.

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