An Endocrinologist’s Perspective: Effects of Disease on Nutrient Metabolism and Muscle Loss

At a Glance

  • Dr. Marcus Goncalves is a fourth year research fellow in Endocrinology, Diabetes, and Metabolism Fellowship at NewYork-Presbyterian/Weill Cornell studying the causes of muscle loss in cancer patients.
  • Goncalves and other fellows receive didactic instruction, clinical training, and conduct research at NewYork-Presbyterian Hospital, Memorial Sloan-Kettering Cancer Center, and the Hospital for Special Surgery.
  • Working in the laboratory of Dr. Lewis C. Cantley, Dr. Goncalves is also interested in muscle loss during critical illness, basic mechanisms of skeletal muscle growth and metabolism, insulin signaling, and developing new radiologic methods to assess skeletal muscle quality and function.

“I pursued medicine to develop a more complete understanding of human physiology and pathophysiology. Cancer is one example where a small cellular change can alter metabolism so greatly that the body loses its ability to maintain essential nutrients like triglyceride and amino acids. This cachexia syndrome causes patients to waste away and die of frailty and immobility. It has no clear diagnostic methodology, no known mechanism, and no FDA-approved treatment.”

— Dr. Marcus D. Goncalves

In 2018, Marcus DaSilva Goncalves, MD, PhD, will end a more than 15-year journey to become a physician-scientist when he completes a four-year research fellowship in the Division of Endocrinology at NewYork-Presbyterian/Weill Cornell Medical Center. In actuality, however, his goal to understand the complex interplay of metabolic organs to store and metabolize nutrients began to take shape in his youth.

Dr. Marcus D. Goncalves

Dr. Marcus D. Goncalves

“This desire started when I was 12 years old and I realized I could modify my own body composition by changing my diet and exercise regimen,” notes Dr. Goncalves. “I searched the fields of nutrition and exercise physiology to learn more about the mechanisms behind these changes but I was not satisfied with the quality of the evidence I found.”

His preoccupation with the subject and the paucity of information led him to Johns Hopkins University as an undergraduate studying biomedical engineering.

“Here I learned the engineering, mathematical, and computational tools that are essential to understanding the feedback regulation of nutrients and metabolic hormones in the body,” says Dr. Goncalves, who started in his freshman year doing laboratory research. “I was involved in a project looking at how yeast cells communicate with each other via small proteins – much like hormones in the body. This was my first insight into hormone function and regulation and my introduction to the basis of endocrinology. I wanted to know which hormones were responsible for regulating muscle and fat in a larger organism with many cells rather than a single-cell microorganism.”

Dr. Goncalves took these tools with him as he moved on to his master’s studies in biomedical engineering at Johns Hopkins and PhD studies in cell biology and physiology at the University of Pennsylvania. At the latter, his research involved investigating the regulation of several types of hormones that regulate skeletal muscle mass and glucose homeostasis, as well as the role of myostatin on muscle growth and metabolism.

“While looking for a lab to join, I was offered a project by an endocrinologist who was also a physician-scientist,” notes Dr. Goncalves. “He was investigating a drug that increases muscle size in a mouse but, for reasons unknown, the mice went on to lose all of their body fat. The project couldn’t have been more perfect for me. The research was focused on a protein called myostatin, which, when you take this protein away, causes the muscles to get much bigger. So it releases a stop signal that’s naturally present.”

He says, “While this has not been proven, I believe myostatin is a muscle hormone that works together with catabolic steroids to break down the muscle fiber. Muscle fibers are the body’s reservoir for amino acids so it makes sense that muscle is called upon to release amino acids in times of metabolic need. When you take the myostatin away, catabolism is being shut down, tipping the balance towards protein synthesis and anabolism.”

“The implications for treatments targeting myostatin are vast,” continues Dr. Goncalves. “Involuntary loss of skeletal muscle (termed sarcopenia) is associated with many common diseases, including sepsis, chronic obstructive pulmonary disease, HIV infection, burn trauma, and cancer.” As proof of principle, Dr. Goncalves participated in a study targeting myostatin’s receptor (activin receptor type IIB) to improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy. Study data showed that targeting activin receptor type IIB improved skeletal muscle mass and functional strength, providing a therapeutic rationale for use of this molecule in treating skeletal myopathies.

During this time, Dr. Goncalves also led research on the differential effects of chemotherapy on the metabolic activity of skeletal muscle in patients with melanoma. Using molecular imaging with [18F]- fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT), the researchers showed that FDG-PET/CT can reveal baseline metabolic differences between different muscles of the body and detect and quantify differential changes in the metabolic activity of skeletal muscle associated with different chemotherapies.

A Concentration on Cachexia

Dr. Goncalves then entered the Medical Science Training Program (MD/PhD program) at the Perelman School of Medicine at the University of Pennsylvania in 2012. “I pursued medicine to develop a more complete understanding of human physiology and pathophysiology,” he notes. “I observed the dramatic effects that disease can have on nutrient metabolism. Cancer is one example where a small cellular change can alter metabolism so greatly that the body loses its ability to maintain essential nutrients like triglyceride and amino acids. This cachexia syndrome causes patients to waste away and die of frailty and immobility. It has no clear diagnostic methodology, no known mechanism, and no FDA-approved treatment.”

Cross-sectional images

Cross-sectional images of the chest taken from two mice with lung cancer: one with cachexia and one without

Following medical school, with his interest in this area solidified, Dr. Goncalves narrowed his attention on studies of the mechanisms that lead to muscle loss in patients with cancer. His ultimate goal is to develop effective treatments that prolong and improve quality of life with a complementary goal of bridging the gap between science and medicine in the field of endocrinology, nutrition, and exercise physiology. “Many clinicians fail to understand the basic mechanisms that control energy balance and many researchers do not appreciate the biopsychosocial approach to medical treatment,” says Dr. Goncalves. As a physician-scientist, and with training that crosses biomedicine, basic science, and patient care, Dr. Goncalves now brings a unique perspective to studying disease-related muscle loss in model organisms and through to clinical trials.

For the past several years, Dr. Goncalves has been an endocrinology research fellow in the laboratory of Lewis C. Cantley, PhD, Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. In addition to muscle loss in cancer, Dr. Goncalves is also interested in muscle loss during critical illness, basic mechanisms of skeletal muscle growth and metabolism, insulin signaling, and developing new radiologic methods to assess skeletal muscle quality and function. The first year of his fellowship was dedicated to patient care, dividing his time between endocrinology consults at NewYork-Presbyterian/Weill Cornell and oncology consults at Memorial Sloan Kettering Cancer Center. He is now deep into the research component of his fellowship, continuing his work on mouse models of cancer and cachexia. He also collaborates with Kenneth P. Olive, PhD, Director of the Small Animal Imaging Shared Resource in the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, on a pancreatic mouse model looking at both histology and metabolism.

“We have a few different genetic models where the mice spontaneously develop tumors,” says Dr. Goncalves. “They all develop the same metabolic disease as patients with cancer. As an endocrinologist, I ask different questions than the muscle-specific or cancer-specific biologists. I’m interested more in skeletal muscle metabolism and why the muscle is breaking down from a metabolic point of view rather than a cancer point of view. Some researchers believe that the muscle breakdown is purely from inflammation. I think that other hormones are altered – especially testosterone, insulin-like growth factor, and cortisol.”

According to Dr. Goncalves, treatments for cancer-induced muscle loss are almost non-existent. “Protein or amino acid supplements are sometimes used which may or may not work. Some groups have tried medications off-label such as beta-blockers or non-steroidal anti-inflammatories. These also have very weak data related to results. So the field is wide open for something that can help – even a little – which can make a big difference in a patient’s quality of life while undergoing cancer treatment.”

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