PHD3 Loss, Fat Metabolism, and Exercise Endurance

Tolerance of exercise and endurance can both decrease with age and declining metabolic health yet physical activity remains a cornerstone of physical and mental health regardless of age. Enzyme systems have received increasing attention for their potential to reduce exercise fatigue and improve endurance by providing the body with access to energy reserves and optimizing their use. Sugars are the primary fuel of cellular processes however, when nutrients are scarce – such as in cases of starvation or extreme exertion – cells switch to breaking down fats for energy. At this time, the mechanisms behind the rewiring of cellular metabolic pathways in response to fluctuations in resource availability are poorly understood.

New research published earlier this month in Cell Metabolism suggests a surprising consequence when one such mechanism is turned off – an increased capacity for endurance exercise. Recently conducted by researchers from the Harvard Medical School, the study revealed that blocking the activity of a fat-regulating enzyme in the muscles of mice could lead to an increased capacity for endurance exercise

Boosting Exercise Endurance in Mice

Led by Marcia Haigis, professor of cell biology at Harvard Medical School, a team of researchers investigated the function of the enzyme prolyl hydroxylase 3 (PHD3) – which they believed played a role in regulating fat metabolism in certain cancers. The study’s authors investigated the impact of PHD3 inhibition in genetically modified mice by carrying out a series of endurance exercise experiments.

Under normal conditions, PHD3 chemically modifies the enzyme ACC2 which prevents fatty acids from entering mitochondria to be broken down into energy. The team of researchers found that blocking PHD3 production in mice resulted in dramatic improvements in fitness measures: mice lacking the PHD3 enzyme ran 40% longer and 50% farther on treadmills and had a higher VO2 max – indicating increased aerobic endurance – than control subjects.

After endurance experiments, the muscles of PHD3-deficient mice revealed heightened rates of fat metabolism and an altered fatty acid composition and metabolic profile. According to the authors, their findings held true in genetically modified mice demonstrating that PHD3 loss in muscle tissues may be sufficient to boost exercise capacity.

PHD3 Enzyme Regulates Metabolic Pathways

After performing a series of molecular analyses to detail precise molecular interactions allowing PHD3 to modify ACC2 and how its activity repressed by AMPK, Haigis and her team reported that PHD3 and AMPK, another enzyme, simultaneously control the activity of ACC2 to regulate fat metabolism depending on energy resource availability.

Their research identified the critical role of the enzyme prolyl hydroxylase 3 (PHD3) in sensing nutrient availability and regulating the ability of muscle cells to metabolize fats, revealing that when nutrients are abundant, PHD3 acts as a brake inhibiting unnecessary fat metabolism that is released during exercise. Whole body or skeletal muscle PHD3 loss enhances acute exercise capacity during endurance exercise experiments.

“The findings shed light on a key mechanism for how cells metabolize fuels and offer clues toward a better understanding of muscle function and fitness,” the authors wrote.

“Understanding this pathway and how our cells metabolize energy and fuels potentially has broad applications in biology, ranging from cancer control to exercise physiology,” senior author Haigis explained. Although, further research is needed to identify whether this pathway can be manipulated in humans to improve muscle function, in the treatment of various diseases, and to better understand how PHD3 inhibition improves exercise capacity.

The latest findings carry implications for a potential novel approach to enhancing exercise performance, treating muscle disorders, as well as developing therapeutic methods for certain cancers in which mutated cells express decreased levels of PHD3. At this time, whether there are any negative effects – including weight loss, blood sugar changes and other metabolic markers – associated with PHD3 loss remains unknown although, this will hopefully be elucidated by future research.

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Common Class of Medications Linked to AD, MCI Risk 

Several types of medications have been linked to mild cognitive impairment and Alzheimer’s disease (AD) risk in older patients over the years. A growing body of evidence points to drugs with anticholinergic effects as particularly dangerous for certain patient demographics. Emerging results from a recent study indicate that there may be a significant association between anticholinergic medications, AD biomarkers, and the incidence of mild cognitive impairment among cognitively normal older adults.

Anticholinergic Medications

Anticholinergic drugs have been widely used for a variety of medical conditions, ranging from allergies and the common cold to the treatment of hypertension. While certain anticholinergic medications require a prescription, others can be easily purchased over the counter.

This class of medications works by blocking acetylcholine, a neurotransmitter critical for memory function, from binding to receptors on certain nerve cells thereby inhibiting parasympathetic nerve impulses, which underlie involuntary muscle movements and bodily functions.

Examining the Relationship 

A team of researchers aimed to determine whether there were any cognitive consequences of anticholinergic medications (aCH) among a group of cognitively normal older patients and whether the interactive effects of genetic and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) risk factors had any influence.

Led by Alexandra Weigand at the UC San Diego School of Medicine, the team of researchers assessed 688 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative with a mean age of 73.5 years. None of the participants presented with any cognitive or memory problems at the time of study inception. Approximately one-third of patients was taking anticholinergic medications with an average of 4.7 aCH drugs per person. The study’s authors administered comprehensive cognitive tests annually for all participants.

Cox regression models were used to examine the risk of progression to mild cognitive impairment (MCI) over a 10-year period, while linear mixed effects models were utilized to evaluate 3-year rates of memory, executive, and language function as related to anticholinergic medication administration.

Association of Anticholinergic Drugs with AD and MCI

According to the study’s findings published in Neurology, participants with AD biomarkers who were taking anticholinergic medications were up to four times more likely to develop mild cognitive impairment than those lacking biomarkers and not taking aCH drugs. Similarly, participants who were at a genetic risk for Alzheimer’s disease who took anticholinergic medications were up to 2.5 times more likely to develop MCI than those without genetic risk factors who were not taking the medications.

Further, linear mixed effects models found that anticholinergic medications predicted a steeper slope of decline in memory and language functions. This was especially true for participants with AD risk factors, in which the effects were exacerbated.

Researchers believe that the association acts in a “double hit manner” :”In the first hit, Alzheimer’s biomarkers indicate that pathology has started to accumulate in and degenerate a small region called the basal forebrain that produces the chemical acetylcholine, which promotes thinking and memory. In the second hit, anticholinergic drugs further deplete the brain’s store of acetylcholine.” Overall, the combined effect can have a severe impact on a patient’s thinking and memory.

Clinical Implications 

The latest findings implicate an increased risk of incident MCI and cognitive decline as related to anticholinergic medications with effects significantly exacerbated in patients with existing genetic risk factors and CSF-based biomarkers. These results “underscore the adverse impact of these drugs on cognition and the need for deprescribing trials, particularly among individuals with elevated risk for AD,” the study’s authors wrote, emphasizing the importance of further evaluation to determine whether reductions in drug usage can lead to reductions in MCI progression.

However, the researchers also noted that anticholinergic medications were being taken at levels much higher than the lowest effective dose recommended for older patients; 57% of participants were taking twice the recommended dosage while 18% were taking at least four times the recommended dose.

As the findings suggest, reducing anticholinergic drug consumption may help delay age-related cognitive decline. According to senior author and associate professor at the UC San Diego School of Medicine Lisa Delano-Wood, PhD, the latest study “suggests that reducing anticholinergic drug use before cognitive problems appear may be important for preventing future negative effects on memory and thinking skills, especially for people at greater risk for Alzheimer’s disease.”

While the current evidence indicates a clear association between anticholinergic medications and cognitive effects, further research efforts are needed to determine whether these agents are able to accelerate cognitive changes or lead to the development of Alzheimer’s disease and other neurodegenerative disorders.