Enhanced skeletal muscle as a novel determinant of CNS aging and Alzheimer’s disease
Alzheimer’s Afternoons Seminar Series (April 21)
Dr. Constanza J. Cortes, Brain Aging Physiology Lab, University of Alabama BirminghamTakeaway:
A robust lysosomal waste disposal system in muscle tissue promotes healthy cognition in aging mice and those predisposed to Alzheimer’s disease. The link seems to be the secretion of myokines by young, exercised muscle tissue, which circulates to the central nervous system and supports brain health.
Dr. Cortes is interested in how distant tissues effect brain aging and presented unpublished work for her seminar. She began by reminding us of the nine hallmarks of aging, described by:López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–1217. doi:10.1016/j.cell.2013.05.039 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/ See figure 1.
She pointed out that seven of these nine marks of aging are involved in Alzheimer’s disease. Her interests focus on three: loss of proteostatis, deregulated nutrient sensing, and mitochondrial dysfunction. Here she will talk mainly about proteostasis.
Proteostatis, or “protein homeostasis”, involves all of protein metabolism, folding, cycling, degradation, and aggregation occurring in young, healthy cells and tissues – as described in Figure 3 of the article above. Dr. Cortes explained that aging causes a loss of proteostasis, such as decrease in production of protein chaperones and a decrease in appropriate protein degradation. This forces proteins into the “misfolding pathway”. The accumulation of protein inclusions can be observed, especially in neurons. This occurs in several neurodegenerative diseases, including Huntington’s, Parkinson’s, and Alzheimer’s disease.
She observed that altering (“tweeking”) proteostasis in one tissue of the body can have effects in other, distant tissues. This was first observed in simple model organisms, such as worms and fruit flies. The signal transmitting these effects was found to be insulin-like peptides.
Insulin-like peptides, also called insulin-like growth factors (IGFs), are proteins with high sequence similarity to insulin which cells use to communicate with one another and adapt to their environment.
Dr. Cortes mentioned that these peptides seem to support healthy proteostatis and are associated with longevity, at least in these simple model organisms.
What about in mammals? She reminded us that there are only two interventions known to delay aging phenotypes in all animals, including mammals: exercise and dietary restriction. While the exact mechanisms for these effects are unclear, both delay aging metabolic phenotypes, including the loss of proteostasis.
One particular tissue, skeletal muscle (SM), is especially influential in secreting these types of signals and helping to maintain body-wide proteostasis. Young, healthy, and active SM seems to benefit signaling via the mTOR, IIS, AMPK, PGC1α pathways, for example. An increase in muscle bioenergetics can be observed, and skeletal muscle autophagy is often improved. In short, SM acts as an endocrine organ; it secretes signals called myokines (skeletal muscle hormones) to communicate with other organs and organ systems, such as the liver, pancreas, and adipose tissues.
To test this link between muscles and other organs, especially the brain, Dr. Cortes focused on transcription factor EB (TFEB), which regulates lysosomal function and autophagy.
For those unfamiliar with this molecule:
Lysosomes are bubble-like organelles in the cell cytoplasm containing degradative enzymes. They are a part of the cell’s waste disposal system, whereby compounds taken up by endocytosis or autophagy are broken down.
TFEB is called “a master gene for lysosomal biogenesis”. It controls the production of lysosomal hydrolases, membrane proteins and genes involved in autophagy.
When the cell is starving or in certain diseased states, TFEB migrates from the cytoplasm to the nucleus, resulting in the activation of many target genes.
Higher TFEB production usually results in more lysosomes being produced and more autophagy.
When researchers “overexpress” TFEB overexpression in cells and mouse models of Huntington’s, Parkinson’s, and Alzheimer’s diseases, waste products are degraded the disease phenotypes are reduced.
Dr. Cortes pointed out that when wild-type mice are starved TFEB expression is increased in skeletal muscle. She wondered if this change in SM could benefit the brain.First tests: +TFEB mice
To test this, she created a new mouse model which expressed the human TFEB gene “on demand”, but only in SM. This meant that TFEB protein levels would be 3-5x higher in the SM of these mice, when the system was triggered.
She finds that this seems to increase autophagy, or rather cellular markers of autophagy, by ~20-30%. The normal age-related problems seen in aging mice, including the presence of aggregated proteins in SM tissues, did not occur in these +TFEB mice.
An interesting note: Dr. Cortes pointed out that the protein aggregations and inclusions occurring in aging muscles also occur in skin cells, causing “age spots”.
In short, +TFEB mice had muscles that seemed younger; they looked like 6-month old muscles instead of 16-month old muscles (the difference between young adult and aged mice). It seems to prevent muscle aging.
Cell metabolism was altered as well. In SM tissues +TFEB mice had:
• higher levels of proteins involved, directly and indirectly, in mitochondrial oxidative phosphorylation (OXPHOS)
• larger mitochondria
• increased glucose processing and accumulation of glycogen
• Higher levels of many enzymes involved in glycolysis
• Improved OXPHOS capacity, which did not decrease with age (as it normally does)
• Some myokine levels were increased
• Some markers of inflammation (e.g., IL6) were reducedWhat about the brain? Were any of these benefits occurring in CNS tissue?
Yes, even though the +TFEB gene was only expressed in SM, some similar changes were observed in the brains of 18 month old mice.
• Proteostasis proteins were more abundant.
• Increases in mitochondrial autophagy were observed.
• Improvements in lysosomal function – observed via the clearing of lipofuscin in lysosomes - were also noted.
• Cognition was also improved in these +TFEB mice. Performance in Barnes maze and novel object recognition tests were improved.
So, improved proteostasis in SM leads to better muscle health during aging, a “young” muscle secretome, neuroprotection, and better cognition later in life….at least for otherwise healthy mice.Second tests: does this help mice suffering from Alzheimer’s disease-like pathologies?
There are reasons to believe it might. Skeletal muscle alteration is a reported characteristic of AD. Dr. Cortes noted that the disease is associated with lower muscle mass and function in older patients. Higher SM mass has been correlated with higher brain volumes during AD. And higher muscle mass in older patients is associated with a lower risk of developing AD. In mouse models of AD, exercise which caused the release of myokines – those circulating signals from muscle tissues - improve memory, as indicated in this 2019 article: Lourenco, M.V., Frozza, R.L., de Freitas, G.B. et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat Med 25, 165–175 (2019). https://doi.org/10.1038/s41591-018-0275-4
Dr. Cortes thinks that her +TFEB mice get the benefits of exercise without the actual exercise because of these circulating signals. To test this, she linked the circulatory systems of different strain of mice, by a surgical technique called parabiosis.
Parabiosis is “the anatomical joining of two individuals, especially artificially in physiological research”.
Her group used mice that are models of AD (PS19 tau mice) and the previously mentioned +TFEB mice. These mice were connected, sharing blood and presumably the myokines, at the ages of 3-6 months, when the AD-like pathology of PS19 mice would normally develop.
• PS19 mice developed the expected symptoms of AD.
• But PS19 mice “parabiosed” – sharing a circulatory system – with +TFEB mice did not. Specifically, they had lower levels of p-tau and fewer “rogue” microglia.
The group is now examining global gene expression, specially, of hippocampus tissue, for these animals.
Four relatives with AD. Concerned, but hopeful. Introverted, but will talk about science.