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Each year, more money is spent in the U.S. on musculoskeletal pain than on heart disease and diabetes combined. Exercise physiologist Keith Baar, a professor of Neurobiology, Physiology and Behavior and Physiology and Membrane Biology, is working to change that.

“My lab is concerned with helping people move well throughout their lives,” said Baar. “We’re using an understanding of basic science principles to change a lot of how physical therapy is done. If we can help people move better, we can decrease diseases like diabetes and heart disease. In fact, if you rupture your ACL, you’re 50% more likely to have a heart attack than somebody who hasn’t.”

From basic research to the clinic, gym, and track

Baar’s lab uses a combination of methods to understand how muscles, tendons, and ligaments respond to exercise and nutrition, including molecular and genetic studies, rat models, and human studies.

Baar, who joined UC Davis in 2009, first began studying exercise physiology to understand his own limitations as an athlete.

“I was a very good athlete, and I wanted to know why I wasn’t a great athlete,” said Baar. “A lot of people enter my field to try and figure out what’s holding them back from performing at the world-class level.”

And though he often works with elite athletes — including professional rock climbers, the Denver Broncos, USA Track and Field, and the Chelsea football club — Baar’s work applies to everyone.

“In the last 10 years, my lab has been shifting towards studying tendons and ligaments, because more than 70% of us will suffer a significant tendon injury during our life that will limit our ability to do the things we love,” said Baar.

Exercising smarter, not harder

Baar’s lab has shown that static, controlled forms of exercise, such as planks or wall sits, can be just as powerful as high impact exercises like running. Specifically, they’ve shown that holding static positions for 10 to 30 seconds at a time — which is known as isometric exercise — can help people recover completely from tendon and ligament injuries, which was previously thought to be impossible. During these longer holds, your tendons begin to relax, which means your muscles have to work harder to hold you in place. At the molecular level, this type of exercise stimulates muscle, tendon, and ligament production and alters how genes are switched on or off within the tissues.

“Isometric exercises can fix tendons and ligaments, even though people thought for years that you couldn’t fix these tissues,” said Baar. “We’ve shown that two 15-minute isometric exercise sessions – one in the morning and one in the evening – can actually yield greater benefits than a single 30-minute standard PT session,” said Baar.

These exercises are also a good entry point for people who are older, new to exercise, or who have an underlying metabolic condition. “If grandma wants to maintain the daily routine she’s always had, these are the things that she can do to get stronger and keep her activity level the same,” said Baar.

Lab-grown ligaments

To better understand these tissues, Baar and his team developed a way to grow them from the remnants of human ACL reconstructive surgeries performed at the UC Davis Medical Center.

“From that little piece of ACL, we can make about a thousand engineered ligaments,” said Baar. “And from there, we can exercise them, we can give them different nutrition, we can give them drugs, we can look at their gene expression and which proteins they make — we basically have total control over these little engineered ligaments.”

Using these lab-grown ligaments, Baar’s team showed that tendons and ligaments stop responding to exercise after only about ten minutes.

“Your bones, tendons, ligaments, and cartilage stop getting the signal to get stronger after about five or ten minutes of exercise,” said Baar. “After that, they accumulate more wear and tear, but get no further signal to get better. We’ve used this knowledge to inform our recommendations for elite athletes who’ve experienced injury. Instead of removing training, we add a small amount of training that’s optimized for the connective tissues, and that keeps them healthy and allows them to train harder for longer.”

Baar’s work has been funded by the National Institutes of Health as well as donations from the Clara Wu and Joe Tsai Foundation and Human Performance Alliance. His research has utilized several UC Davis research core facilities, including UC Davis Genome Center and the Bioinformatics Core Facility. 

In a scientific first, researchers from Vanderbilt University and the University of California, San Diego, have generated a high-resolution metabolic “map” of how cells orchestrate glucose processing, revealing a hidden world where organelles and molecular complexes collaborate when responding to a rush of nutrients. This new study, published in Nature Communications, has redefined how glucose metabolism is visualized at the single-cell level. The pioneering work provides both a new method and insights into an organizational and molecular framework that can be used to study how metabolic processes are disrupted in diseases like diabetes, obesity, and cancer, as well as in aging and neurodegeneration.

“This is a new field-we are at the forefront by integrating multiple microscopy modes into sophisticated pipelines to measure the fate of glucose atoms, from whole animals to organelles, and to show the underlying subcellular architecture associated with these processes in cells,” Rafael Arrojo e Drigo said. Arrojo e Drigo is an assistant professor of molecular physiology and biophysics and the corresponding author of the study. “We expect that this advance will propel a new program that exploits these advanced investigational strategies to study and better understand how nutrient metabolism is organized within the highly structured domains of cells and tissues, which allows for the precise regulation of organ function in the context of whole-animal physiology.”

To date, what scientists know about how cells process nutrients like glucose has been derived from bulk metabolomics. Using metabolomics, researchers can analyze an entire set of small molecules within a biological sample, such as a tissue, but it’s done without consideration of the specific spatial or subcellular contexts in which they occur.

These bulk strategies do not reveal the spatial characteristics of cell metabolism at the single-cell level or how these aspects relate to the location of cells and organelles within the complexity of the tissue they reside within.”

Rafael Arrojo e Drigo, assistant professor of molecular physiology and biophysics and corresponding author of the study

This gap in the field’s understanding drove a multidisciplinary team from Vanderbilt, the Vanderbilt University Medical Center, and UCSD to combine stable isotope tracing, multi-scale microscopy, and AI-powered image analysis to map glucose metabolites at animal, tissue, cellular, and organellar scales. The Vanderbilt team was led by co-first authors Christopher Acree and Aliyah Habashy from the Arrojo e Drigo lab and included scientists from the Vanderbilt Mouse Metabolic Phenotyping Center, the Mass Spectrometry Research Center, the Department of Cell and Developmental Biology, and the VUMC Department of Surgery. Researchers from Mark Ellisman’s group at the National Center for Microscopy and Imaging Research at UCSD rounded out the collaboration.

Together, they determined the spatial organization of glucose metabolites, from inside whole animals to within liver cells and even in individual mitochondria. Using isotopically labeled glucose infusions in live mice, the researchers mapped how glucose-derived carbons were incorporated into glycogen, lipid droplets, and other cellular components over time.

Among the major discoveries of this study, the team uncovered a previously unrecognized structural and functional interaction between lipid droplets and glycogen synthesis. In addition, the researchers mapped how contacts between mitochondria and the endoplasmic reticulum-two key organelles involved in energy production and nutrient sensing-shift dynamically in response to changes in blood glucose levels. These mitochondria-ER contacts form part of a broader organelle network that coordinates metabolic responses within the cell. By charting the timeline of these interactions, the study offers new insights into how organelles reorganize to adapt to different metabolic states, shedding light on fundamental mechanisms of glucose metabolism and cellular energy balance.

This breakthrough was made possible by Vanderbilt’s characteristic interdisciplinary environment and the multi-scale, multi-modal imaging thrust of the NCMIR, an alliance that brought together experts in stable isotope tracing, in vivo animal metabolism, mass spectrometry imaging, AI, and computational modeling, Arrojo e Drigo said. Looking ahead, the team hopes to understand how the spatial organization of nutrients inside cells contributes to metabolic health and disease.