Mitochondrial Function, Obesity, and Personalized Lifestyle Medicine

Abstract

The future for designing specific interventions targeting improvement in mitochondrial function employing personalized lifestyle intervention is bright given the significant progress that has been made in the field since early investigations in the mid-1980s. This progress is exemplified by the 2017 publication of a controlled exercise and diet intervention trial in obese adults that demonstrated significant improvement in energy, strength, peak oxygen consumption, quality of life, and bone mineral density after the tailored aerobic and resistance exercise program and calorie controlled diet. Being a part of this evolving field of mitochondrial function has been a wonderful experience—one that I have come to more fully appreciate as I look back with a historical perspective on my 30 years of involvement in personalized lifestyle medicine.

During the 1980s, the role of mitochondrial function in health and disease was becoming better recognized through important work on mitochondrial DNA and various diseases. Among the key findings of that era was the discovery that mitochondrial DNA mutations were associated with various neuromuscular diseases that had diverse phenotypic presentations, including myopathy, fatigability, and exercise intolerance.^1-3 That work served as the foundation for ongoing research and even contemporary findings, such as the concept that mitochondrial defects are associated with metabolic alterations that may influence the etiology of type 2 diabetes and hearing loss.^4,5

Phosphorus-31 nuclear magnetic resonance spectroscopy (P-31 NMR) was a technology developed to assess the metabolic properties of different tissues and it has been essential to advancing the field of mitochondrial research. Phosphorus-31 is a naturally occurring nonradioactive isotope of phosphorus that chemists define as a having a non-zero nuclear spin. Because phosphorus-31 is found naturally in high-energy mitochondrial biochemical intermediates including adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP), phosphocreatine (PCr), and inorganic phosphate (Pi), P-31 NMR analysis can be used to noninvasively measure mitochondrial bioenergetics.⁶ Using P-31 NMR technology to interrogate mitochondrial function involves having an individual place their wrist, arm, or leg in the path of the large magnet within the instrument and exercise this muscle under controlled experimental conditions.^7,8 The availability of P-31 NMR in the 1980s resulted in a rapid increase in published studies on mitochondrial function in humans at rest and after exercise.^9-11 These studies included examination of mitochondrial function in chronic alcoholics,¹² the wrist flexor muscles of college rowers,¹³ and muscle functional status in patients with fibromyalgia.¹⁴

By looking at the phosphorus-containing metabolites in an individual’s muscle at rest and after exercise, the degree of response of the muscle mitochondria to exercise stress can be determined.¹⁵ Researchers can use this measurement as a tool for interpretation of an individual’s genetic mitochondrial activity, fitness level, nutritional status, and exposure to toxins that inhibit mitochondrial function. Studies have shown, for instance, that use of antiretroviral drugs that are known mitochondrial toxins can result in significant changes in bioenergetics as measured by P-31 NMR.¹⁶

In 1985, Menshikova et al,¹⁷ from the Division of Endocrinology and Metabolism at the University of Pittsburgh School of Medicine, published a paper demonstrating that a specific diet and exercise program for obese individuals resulted not only in weight loss, but also mitochondrial biogenesis and increased mitochondrial bioenergetics as evidenced by increased metabolic activity of the mitochondrial electron transport chain. Mitochondria generate energy for cellular energy processes by producing ATP through oxidative phosphorylation of fats, proteins, and carbohydrates, which are diet-derived macronutrients. This mitochondrial activity is highly dependent on the quality of the diet and the sufficiency of vitamin and mineral-derived cofactors and other essential nutrients, as well as the fitness status of the individual.

At the time Menshikova’s work was published, the prevailing view was that a calorie-restricted diet would result in reduced mitochondrial activity and fat metabolism.¹⁷ These new findings encouraged investigators to design and execute additional studies to evaluate the effect of various types of calorie restricted diets and exercise programs on mitochondrial function, obesity, and metabolic status.

Evaluation of the Effect of a Lifestyle Medicine Program on Mitochondrial Function and Obesity

Intrigued and excited by this research on the interrelationship among mitochondrial function, obesity, and lifestyle factors that I was reading about in the medical literature of the era, the research group I was leading in the mid-1980s began exploring the effect of various diet compositions on metabolism in obese humans.¹⁸ In 1986, we engaged in a research study to evaluate the effect of a specific nutrient-fortified, fiber-enriched, calorie-restricted diet and exercise program that was designed around the concept of supporting mitochondrial function. This 12-week intervention pilot study enrolled 65 women with body mass indices (BMIs) ranging from 30 to 38 kg/m² who had a history of difficulty in reducing their BMI. In these study participants, this pilot program resulted in significant improvement in BMI, metabolic parameters of insulin sensitivity and lipid metabolism, marked increases in fitness, and reduction in fatigue. The most remarkable finding, however, was that all participants in the study lost considerable fat mass, but many of them gained fat-free mass. After considering various potential reasons for this result, our leading hypothesis was that the program may have positively affected mitochondrial function in a manner that resulted in selective fat loss and increased muscle mass.¹⁹ Our reasoning was that improved mitochondrial energy expenditure in muscle cells coupled with enhanced brown fat mitochondrial thermogenesis could have accounted for the selective fat loss, while reduction of intramyocellular lipotoxicity could have accounted for the increased muscle protein synthesis as a consequence of the specific diet and exercise program; this is a concept supported by other studies.^20-22

The results of this first trial stimulated us to design a follow-up study focused on the evaluation of the effect of the diet program on mitochondrial function in modestly overweight women. When I attended a meeting of the American College of Nutrition in 1988, I had the great fortune of meeting Dr Robert Hackman, who was a nutrition professor at the University of Oregon at that time, and Dr Richard Brown, President of LEAP, Inc. They shared my interest in evaluating the role of diet and exercise on mitochondrial function in obese individuals. I learned that Dr Brown’s company had just installed 2 Tesla P-31 NMR instruments in Eugene, Oregon, and that Hackman and Brown were looking for sponsorship of a diet and exercise study using this new equipment to assess mitochondrial function. We made the decision to collaborate on a study that would evaluate body composition, resting energy expenditure, and mitochondrial function in exercising muscle before and after the intervention with the program designed by my team in women with elevated BMI who were not diabetic.

Thirty women between the ages of 23 and 39 years, each with 28% to 39% body fat, were recruited for the study. They had to be nonsmokers, not regularly engaged in exercise, who also had no history of dieting for at least 6 months and no disease symptoms. Before the initiation of the study, all participants had their dietary intake measured with a 3-day diet diary for analysis of baseline nutrient intake. The study itself was a 7-week lifestyle medicine intervention trial that consisted of our moderate calorie-restricted, low-fat diet plan (1100 calories/day); daily consumption of 2 nutrient-fortified meal supplement shakes (300 calorie/day); a progressive walking program; and a weekly 1-hour group meeting. The exercise component of the program was based on the principles of target heart rate; it consisted of 20 minutes of daily brisk walking at 60% to 85% of the participant’s target heart rate.

Mitochondrial function was assessed using in vivo phosphorus-31 NMR with a 2.0 Tesla superconducting magnet designed to allow for the participants to have their forearm muscle be exercised through flexion while in the probe of the machine. Baseline-corrected and curve-fitted NMR spectra were integrated, and the concentration of Pi, ATP, and PCr were determined. Data on the influence of exercise and diet on mitochondrial function was calculated as the ratio between Pi to PCr under controlled exercise and recovery conditions while the participant had their forearm in the machine. Data on each participant was computed from 3 repetitions of the exercise challenge with each exercise challenge followed by 5 minutes of rest.

The results of the 7-week intervention trial demonstrated that all but 1 of the subjects who completed the trial had lost weight, ranging from 5.7 to 22 pounds (12.57 to 48.5 kg). In addition, all but 1 of the participants had a decline in body fat, ranging from 0.04% to 10.1%. Loss of fat ranged from 2 to 25 pounds (0.91 to 11.34 kg). Increase in fat-free mass was seen in a majority of the participants, ranging from 0.5 to 7.5 pounds (0.23 to 3.40 kg).²³ This observation of increased muscle mass after weight loss was unexpected but reproduced the results that we had observed in the initial pilot study of the program.

With regard to the assessment of mitochondrial function in study participants, PCr concentrations in muscle declined during exercise (as would be expected) and were partially repleted during the recovery phase when the participant was at rest in the P-31 NMR machine after exercising their forearm muscles to exhaustion. PCr represents an energy storage metabolite in the mitochondria and its depletion and repletion is related to mitochondrial energy dynamics. The ratio of Pi to PCr was used as a marker of the bioenergetic status of the mitochondria in the forearm muscle before and after exercise. As demonstrated by the 2 studies I was involved with, after 4 and 7 weeks of intervention with the specific lifestyle medicine program respectively, there was improvement in mitochondrial bioenergetics at rest as well as a strong statistical correlation between the amount of fat lost and the improvement in mitochondrial function after exercise challenge. This result indicated that the specific lifestyle medicine program resulted in improved mitochondrial function and the improvement in metabolic fitness as evidenced by the increase in tolerance to a forearm exercise challenge.

In support of these observations, Argov et al²⁵ in 1991 published a study in which the results—like Menshikova— demonstrated, by P-31 NMR, the positive effects on mitochondrial bioenergetics of a specific diet and exercise program in overweight individuals. A decade later, Toledo et al²⁶ also reported that a specific calorie restricted diet in combination with an aerobic exercise program resulted in increased mitochondrial activity during weight loss.

The improvement in mitochondrial Pi/PCr ratios observed in this study were likely to represent systemic rather than improvement in local skeletal muscle energy metabolism or fitness in that forearm exercises and strength training were not a part of the intervention program, and, therefore, a localized training effect was not likely. After all of the data was collected and analyzed, Hackman et al²⁴ came to the following conclusions about the impact of the lifestyle medicine program they studied: “Preservation of the Pi/PCr ratio under the three test conditions suggests a general protection of skeletal muscle mitochondrial energy production in conjunction with significant losses of body weight and fat mass.” An interesting side note: Analysis of the preintervention diet of the participants in the Hackman/Brown study identified a consistent trend of vitamin and mineral intakes below the recommended daily intake (RDI) levels. A number of specific nutrients that are known to be important for supporting mitochondrial function were low in a majority of the participants, including magnesium, chromium, zinc, vitamin B₁₂, folate, and vitamin B₆, which were all less than 80% of the recommended intake for the majority of women entering the study. Because the intervention program involved the consumption of a balanced, moderately calorie-restricted diet along with the specific nutrient-fortified meal supplement, participants who followed the plan exceeded all levels of RDI micronutrient intake. Hackman et al²⁴ summarized the results of this intervention trial this way: “These results suggest that this low-fat, moderate energy diet plan, coupled with a vitamin-mineral drink and a vigorous exercise plan, may be helpful in promoting loss of fat mass while preserving skeletal muscle mitochondrial energy metabolism and fat free mass.”

From the Bleeding Edge to the Leading Edge

Since 1990, the field of mitochondrial metabolism and its relationship to exercise intolerance and fatigue has advanced remarkably.^27,28 This advancement has been aided by an increase in the application of P-31 NMR assessment of in situ mitochondrial function in skeletal muscle.²⁹ It is now recognized that specific types of calorie restricted diets can have a positive impact on improving mitochondrial metabolism.³⁰ This is a validation of hypotheses put forth by my research group and our associates based on data from intervention studies. Furthermore, a review of recent human dietary intervention trials using moderate calorie restricted diet and exercise plans demonstrates improvement in skeletal muscle mitochondrial function.^31-33 In a 2013 review paper, authors Toledo and Goodpaster state: “The available literature strongly suggests that the lower mitochondrial capacity associated with obesity, type 2 diabetes and aging is not an irreversible lesion.” They continue: “Studies of diet and exercise training have advanced our understanding of the link between mitochondrial oxidative capacity and insulin resistance in obesity, type 2 diabetes, and aging.”³⁴

Recent studies have also demonstrated that very low calorie or imbalanced diet plans or fasting can have an adverse influence on mitochondrial oxidative function.³⁵ Diet plans that alter the gut microbiome in such a way as to induce metabolic endotoxicity (due to either the increased intake of the saturated fat palmitic acid or low intake of prebiotic fiber that results in increased production of lipopolysaccharide in the gut) contribute to a reduction in muscle mitochondrial function through activation of toll-like receptor 4.³⁶ This finding may, in part, provide an explanation for the emerging connection between the alteration in the gut microbiome and obesity.³⁷ It has been demonstrated that the short chain fatty acid butyrate, which is the product of fermentation in the gut of dietary fiber by a healthy microbiome, improves muscle mitochondrial function, and reduces the risk to obesity.³⁸

There are numerous reports of other dietary factors— including phytochemicals such as allyl isothiocyanate found in cruciferous vegetables and resveratrol found in peanut and grape skins, acylcarnitines found in animal products, and nicotinamide riboside found in nuts and seeds—contributing to improvement in mitochondrial function.^39-41

Looking Back, Looking Forward

Time is a wonderful teacher of truth. Our understanding of the ways that diet and exercise influence mitochondrial function has expanded significantly since the 1980s and with this evolution in thinking has come a recognition of the links between mitochondrial function and obesity, type 2 diabetes, and other chronic diseases of aging.⁴² It is now widely accepted that P-31 NMR is a tool that can be used to measure in situ performance of mitochondria in health and disease states.⁴³ It is also now well recognized that alterations in Pi/PCr ratio in skeletal muscle is indicative of the mitochondrial connection to obesity.⁴⁴ Last, it has become better recognized that specific nutrients, such as vitamin D and magnesium, influence mitochondrial function as measured using P-31 NMR.^45,46

The future for designing specific interventions targeting improvement in mitochondrial function employing personalized lifestyle intervention is bright given the significant progress that has been made in the field since early investigations in the mid-1980s.⁴⁷ This progress is exemplified by the 2017 publication of a controlled exercise and diet intervention trial in obese adults that demonstrated significant improvement in energy, strength, peak oxygen consumption, quality of life, and bone mineral density after the tailored aerobic and resistance exercise program and calorie controlled diet.⁴⁸ Being a part of this evolving field of mitochondrial function has been a wonderful experience—one that I have come to more fully appreciate as I look back with a historical perspective on my 30 years of involvement in personalized lifestyle medicine.

Biography

Jeffrey Bland, PhD,, FACN, FACB, is the president and founder of the Personalized Lifestyle Medicine Institute in Seattle, Washington. He has been an internationally recognized leader in nutrition medicine for more than 25 years. Dr Bland is the cofounder of the Institute for Functional Medicine (IFM) and is chairman emeritus of IFM’s Board of Directors. He is the author of the 2014 book The Disease Delusion: Conquering the Causes of Chronic Illness for a Healthier, Longer, and Happier Life.