Researchers have discovered that an intracellular protein degradation system may be crucial to normal metabolism and the response to exercise. To help get rid of imperfect proteins and aging cellular components, and in some cases to modulate levels of intracellular factors, a cell can engulf portions of itself, target the damaged contents for breakdown, and recycle undamaged components for reuse. This process is called autophagy. While autophagy occurs at a basal level under normal circumstances, it is also stimulated by starvation and other stressors, enabling cells to adapt to changing conditions and needs. Scientists studying this process in mice recently found that muscle cells turn up autophagy in response to exercise. Intriguingly, when mice with mutations that hinder such stimulus-induced autophagy ran on a treadmill without prior exercise training, they showed lower endurance than normal mice. Also, while strenuous exercise normally induces changes in skeletal muscle that help it use glucose more efficiently, the autophagy-deficient mice did not show those changes. Autophagy was particularly important for achieving the metabolic benefit of long-term exercise training, in the context of obesity. Researchers found that while exercise protected normal mice from elevated glucose levels induced by a high-fat diet, it did not give autophagy-deficient mice the same protection. The autophagy-deficient mice also did not show exercise-induced improvements in levels of cholesterol and triglycerides (a type of fat) that were seen in normal mice. These findings suggest that autophagy plays a role in conferring the health benefits of exercise.
In addition to evidence that autophagy helps the body respond to exercise, researchers found it is also needed to produce a signal that the body has consumed enough food. Scientists studied the role of autophagy in the hypothalamus, the region of the brain central to control of energy balance—regulating energy intake (as food calories) and expenditure (burning calories to maintain basic body functions, do work, or generate heat).
Certain cells in the hypothalamus generate the hormone α-melanocyte-stimulating hormone (α-MSH) that signals the brain to curtail eating and promote calorie burning. Mice genetically engineered to lack autophagy in just these brain cells showed altered levels of molecular factors important to energy balance, including reduced levels of α-MSH. These mice gained more fat weight than normal mice when fed a high-fat diet, and appeared to have problems with mobilizing fat from fat cells for use as an energy source when fasted. They also showed impaired glucose tolerance. Similar problems with brain-derived hormone levels and with fat mobilization occur with older age in mice—raising the possibility that some of the metabolic problems associated with aging may be due partly to loss of autophagy.
Together, these papers suggest that autophagy, already known to help protect against cancer and some other diseases, also has a key role in counteracting some of the dangerous metabolic consequences of obesity, including type 2 diabetes risk. If borne out through further research, strategies to mimic or manipulate autophagy may prove beneficial in preventing or treating these conditions.
He C, Bassik MC, Moresi V, et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481: 511-515, 2012.
Kaushik S, Arias E, Kwon H, et al. Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep 13: 258-265, 2012.