Biologists reveal how obesity damages skeletal muscle metabolism

Decreased metabolism and skeletal muscle endurance is commonly seen in obese patients, but the underlying mechanism is not well understood. Research team led by Dr. Chi Bun Chan, assistant professor in the School of Biological Sciences, Faculty of Science at the University of Hong Kong (HKU), discovers new mechanism to explain how obesity compromises functions skeletal muscle and offers potential treatment for the disease. The research results were recently published in the journal Autophagy.

Obesity is a metabolic disorder that is increasing in prevalence in modern society. Since the 1970s, the global number of obese people has tripled and reached 650 million (approximately 13% of the total world population) in 2016. It is well known that obesity causes adverse effects in several human organs and causes many chronic disorders such as diabetes, hypertension, fatty liver and atherosclerosis. Fat metabolism in the skeletal muscle of obese patients is slower than that of healthy people, which scientists say is a consequence of the abnormal functions of mitochondria (the powerhouses of a cell that convert nutrients into biological energy). However, how obesity impairs the activity of mitochondria is a long-unresolved question.

To study the functional impacts of obesity on skeletal muscle, Dr. Chan’s team developed a special obesified mouse model by deleting the brain-derived neurotrophic factor (BDNF) gene exclusively in their skeletal muscle. BDNF was originally identified as an important growth factor for maintaining the survival and activities of neurons. Recent studies have suggested that BDNF is also a protein secreted by muscles (i.e., myokine), but its physiological significance is unknown.

For the first time, Dr. Chan’s team found that obesity reduced the amount of BDNF in the skeletal muscle of mice. They also observed that mice without BDNF in their muscles, called “MBKO” (Muscle-specific BDNF Knockout), gained more body weight and developed more severe insulin resistance when the animals were fed a diet rich in protein. fats. In addition, the research team found that the MBKO mice have a lower energy expenditure than their control cohort.

Using a number of biochemical, histological, metabolomic and molecular analyzes, the research team further demonstrated that the mitochondria in the muscles of MBKO mice were unable to recycle, resulting in the buildup of damaged mitochondria. in tissues. As a result, lipid metabolism in muscle of MBKO mice was slowed down, resulting in increased accumulation of lipids to interfere with insulin sensitivity.

“Obviously, muscle-derived BDNF is a weight control protein by increasing energy expenditure and maintaining insulin sensitivity,” said Dr. Chan.

“BDNF has long been considered a localized peptide in the brain, and its importance in peripheral tissues has been underestimated. Our study provides new insight into this area, and we hope to be able to unlock more functions of this myokine by using our MBKO mice, ”says Dr. Chan added.

In addition to animal studies, Dr. Chan’s team also used cultured cell models to identify the molecular mechanism of faulty mitochondrial turnover in BDNF-deficient muscle cells. They found that muscle-secreted BDNF uses protein kinase activated by AMPK, the well-known energy scavenger in cells, to trigger the Parkin / PINK1 pathway to induce mitophagy (a highly regulated mechanism to recycle cells. materials in cells in response to various challenges) in skeletal muscle.

To extend these results to therapeutic applications, the research team also tested whether the restoration of BDNF signaling in muscle would save the mitochondrial damage induced by obesity. They fed the obese mice with 7,8-dihydroxyflavone, a natural mimetic of bioavailable BDNF in plants (found in the leaves of Godmania aesculifolia, a plant species from South America) currently used in clinical trials of the Alzheimer’s disease, and found that obesity- induced mitochondrial dysfunction was alleviated.

Along with the previous findings that 7,8-DHF is an effective agent for reducing body weight and improving insulin sensitivity in obese mice (Bio chemistry 2015 22: 355-369; Metabolism 2018 87: 113-122), Dr. Chan’s work provides a new explanation for the pernicious nature of obesity and suggests that the BDNF signaling activator such as 7,8-DHF is a potential drug for the treatment of obesity in humans.