Dr. Lanza has six main research projects in the Muscle Physiology and Metabolism Laboratory at Mayo Clinic:
- Adaptive responses to exercise
- Chronic inflammation and its influence on skeletal muscle
- Molecular transducers of physical activity
- Mitochondrial physiology
- Dietary bioactive lipids and skeletal muscle health
Adaptive responses to exercise
The "exercise is medicine" groundswell is fueled by painstaking research demonstrating that exercise has benefits across many organ systems. Exercise forestalls muscle loss in aging and cancer and improves metabolic health by enhancing insulin sensitivity, glucose disposal and mitochondrial function. These benefits have prompted health organizations to recommend exercise at 150 minutes a week.
However, Dr. Lanza believes that these recommendations ignore a fundamental problem: People who stand to benefit most from exercise are often the ones who exhibit a phenomenon known as exercise resistance. These people often exhibit blunted adaptive responses (transcriptional, translational and metabolic) to carefully controlled exercise interventions. Based on emerging literature and preliminary studies, Dr. Lanza believes that chronic inflammation is detrimental to skeletal muscle health and interferes with many of the molecular and adaptive responses to exercise.
The research taking place in our lab is designed out of a want for better understanding of how chronic inflammation influences skeletal muscle biology and the adaptive responses to exercise. If we understand the factors that attenuate exercise responsiveness, it becomes possible to design strategies to overcome exercise resistance and potentiate the adaptive responses to exercise.
The goal isn't to discover an exercise mimetic to replace exercise entirely. Rather, we hope to identify strategies that can be used alongside exercise to enhance adaptations. In many respects, Dr. Lanza disagrees with one-size-fits-all exercise recommendations. He believes that exercise should be carefully prescribed with attention to underlying factors that could be targeted in an individualized way to maximize the health benefits.
Toward this goal, our lab seeks to understand how chronic inflammation influences skeletal muscle physiology and exercise responsiveness. The approach involves a combination of translational studies in humans and basic science approaches in model systems.
Our lab is spearheading ongoing clinical studies with an overall objective of determining how chronic inflammation influences exercise responsiveness, mitochondrial physiology and metabolic function in skeletal muscle in aging, obesity and cancer.
Each of these studies leverages the analytical power of mass spectrometry in concert with administration of stable isotopes to measure in vivo rates of muscle protein synthesis, glucose metabolism and lipid metabolism. Skeletal muscle and adipose tissue biopsies are collected from research participants for the purpose of examining gene expression patterns before and after exercise, mitochondrial physiology and protein signaling events.
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Chronic inflammation and its influence on skeletal muscle
Ongoing laboratory-based experiments are designed to generate mechanistic insights that aren't possible in our clinical studies. For example, our lab is investigating how experimental modulation of various inflammatory pathways influences salient molecular and cellular events in skeletal muscle.
These pathways include:
- Mitochondrial physiology and biogenesis
- Protein synthesis and degradation
- Protein signaling events
- Gene expression patterns
- Endoplasmic reticulum stress and the unfolded protein response
- Immune cell infiltration and macrophage polarization
Molecular transducers of physical activity
Dr. Lanza is one of the principal investigators in a nationwide initiative to generate a molecular map of physical activity. The group is called the Molecular Transducers of Physical Activity Consortium (MoTrPAC). Our lab, in collaboration with the lab of K. Sreekumaran Nair, M.D., Ph.D., at Mayo Clinic is contributing to building this molecular map from the standpoint of extracellular vesicles, or more specifically, exosomes, which are small, membrane-bound vesicles that are found in circulation and originate from many different tissues, including platelets, skeletal muscle, liver and adipose tissue.
As a MoTrPAC Chemical Analysis Site, we are focused on characterizing the molecular cargo (protein, small RNA) of extracellular vesicles and how this cargo is influenced by physical activity. Our lab also is interested in how exosome cargo may be an important means for cell-to-cell communication under pathological conditions such as senescence. Using advanced purification techniques, our lab has been able to optimize exosome isolation from human plasma samples and culture media, followed by proteomic profiling by advanced mass spectrometry techniques and RNA sequencing.
Mitochondria are ubiquitous cellular organelles that provide an abundance of chemical energy that is essential for survival. These organelles also generate reactive oxygen species, which play an important role in cellular signaling and cell death. Comprehensive mitochondrial phenotyping is a cornerstone of the research in the Muscle Physiology and Metabolism Laboratory.
Our lab has established a growing number of cutting-edge assays to evaluate the function of mitochondria from the standpoint of oxygen consumption (respiration), chemical energy production (ATP synthesis) and reactive oxygen species production.
In clinical studies, small biopsies of skeletal muscle or fat are used to isolate mitochondria or prepare small bundles of muscle fibers. The abundance, oxidative capacity and efficiency of mitochondria in these samples are evaluated under carefully controlled conditions using such techniques as high-resolution respirometry, electron microscopy and spectrofluorometry.
In some situations, it's not possible to obtain sufficient tissue for mitochondrial physiology measurements (for example, vulnerable patient populations, inaccessible tissue and repeated measurements). In these situations, our lab leverages the noninvasive techniques of magnetic resonance imaging (MRI) and magnetic resonance (MR) spectroscopy.
MRI allows measurements of muscle area and volume, and MR spectroscopy provides a noninvasive window into skeletal muscle bioenergetics. This imaging technology is also used to noninvasively measure the amount of fat in the muscle and liver, which is a strong predictor of insulin resistance and type 2 diabetes. These techniques are routinely used as part of ongoing clinical studies in our lab and complement ex vivo approaches.
Dietary bioactive lipids and skeletal muscle health
Omega-3 fatty acids are highly abundant in cold-water fish and some plants and widely recognized for their effects on lowering circulating triglycerides. There's also growing recognition that omega-3 fatty acids have anti-inflammatory effects. Both epidemiological studies and preclinical studies suggest that including these types of fats in the diet can lead to metabolic benefits and possibly enhance skeletal muscle function.
Our lab is engaged in studies to identify novel mechanisms to explain potential health benefits of omega-3 fatty acids, particularly in older adults.
Metabolomics is the measurement of small molecules in biological fluids and tissues. There are thousands of different metabolites found in the human metabolome, including naturally occurring compounds such as amino acids, sugars, lipids and organic acids, and chemicals that enter the body though the environment, such as medications, toxins, pollutants and the microbiome.
The analysis of the human metabolome provides important clues about what's happening to various metabolic processes within certain tissues. Our research takes advantage of the ability to analyze these small molecules in tissue samples, blood samples and urine to provide new insights into mechanisms of human disease and potential therapeutics.
Mass spectrometry and nuclear magnetic resonance spectroscopy are two complementary analytical tools used for metabolomics in our research. Mass spectrometry continues to be a cornerstone analytical tool for measuring isotopic enrichment in amino acids, glucose and lipids. Incorporation or dilution of stable isotopes provides unique opportunities for evaluating glucose, amino acids and lipid kinetics in humans in vivo. NMR spectroscopy is a nondestructive approach for metabolite detection that is sought after for its quantitative reproducibility and specificity.
In addition to being the principal investigator of his research lab, Dr. Lanza is the director of the Metabolomics Core at Mayo Clinic, which specializes in these measurements along with qualitative and quantitative metabolomics.
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