Longevity

Longevity Briefs: How Obesity Messes With Muscle Tissue (And How We Might Fix It)

Posted on 7 December 2021

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: Obesity is highly detrimental for pretty much every organ system in the human body, and skeletal muscle is no exception. Fat metabolism (the process of breaking down fats and converting them into energy that can be used by cells) is slower in the muscle tissue of obese patients, leading to a build-up of fat within muscle tissue that is thought to be important in the early stages of type II diabetes. Scientists think this happens because of changes in the mitochondria, the power plants within the cell that are responsible for converting nutrients into energy. However, we still aren’t sure how exactly obesity causes these changes. Previous research has suggested that a growth factor called brain-derived neurotrophic factor (BDNF) is important for regulating mitochondria in muscle tissue, and that it might play a role in the response to muscle cells being overloaded with lipids (fat).

What did the researchers do: In this study, researchers genetically modified mice so that their skeletal muscles lacked the gene needed to produce BDNF. BDNF was originally found to be important for the survival of neurons in the brain, but it has since been found to be secreted by muscle tissue. The researchers observed the effects of a high fat diet on these mice, and observed the function of their mitochondria.

Key takeaway(s) from this research: Mice modified to lack the gene for BDNF gained more weight, became more resistant to insulin (the hormone that controls blood sugar and to which resistance leads to diabetes) and had lower levels of energy expenditure when fed a high-fat diet when compared with control mice. The modified mice also showed signs of dysfunctional mitochondria: division and recycling of defective mitochondria were both found to be impaired, which led to an accumulation of poorly-functioning mitochondria and a build-up of lipids (fat) in muscle tissue when the mice were fed high fat diets. Furthermore, the researchers found that BDNF production in muscle tissue was decreased in obese mice that weren’t genetically modified, suggesting that reduced BDNF provides a link between obesity, mitochondrial dysfunction and lipid accumulation in muscle tissue.

Microscope image showing muscle cells frim normal mice (left) and mice modified to lack BDNF (right). TOMM20 (green) is a stain for mitochondria, LC3 (red) is a stain for ‘recycling complexes’ called autophagolysosomes, and DAPI (blue) is a stain for DNA-containing nuclei. Researchers found that modified mice had more mitochondria in their muscle cells, but that this was due to reduced recycling rather than increased production.
Source

To see if restoring BDNF might have any therapeutic effect, the researchers then gave obese mice 7,8-dihydroxyflavone, a natural BDNF-like compound found in the leaves of a South American plant called Godmania aesculifolia. They found that some of the mitochondrial dysfunction was indeed prevented.

So it seems as though muscle-produced BDNF is important for maintaining healthy mitochondria and therefore a healthy muscle metabolism, and that reduced BDNF production due to overfeeding might explain why obesity harms muscle metabolism. Therapies targeting BDNF production might be able to help preserve metabolic function and reduce the risk of metabolic disease, although that’s likely to be a long way off as this research is still limited to mouse models. Worthy of note is that fasting was previously shown to increase muscle BDNF levels in mice, as the resulting production of mitochondria helps the muscle tissue to transition from glucose to fat as a main fuel source.


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References

Muscle-generated BDNF (brain derived neurotrophic factor) maintains mitochondrial quality control in female mice: https://doi.org/10.1080/15548627.2021.1985257

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