Researchers at the University of Colorado Anschutz have found that healthy yet sedentary individuals show a significant, coordinated drop in muscle mitochondrial function that may precede the development of major diseases like cancer, diabetes and Alzheimer’s.
“Mitochondrial function is the center of metabolic health,” said the study’s senior author Iñigo San Millan, adjoint assistant professor in the Division of Endocrinology, Metabolism and Diabetes at CU Anschutz. “If you are 40, healthy and sedentary, it is likely that you already have something going on inside your cells that will likely come back to haunt you in 10 or 15 years.”
The study specifically noted that mitochondria, which process energy within cells, showed a significantly decreased capacity to burn both sugar and fat in healthy individuals who get less than the recommended 150 minutes of exercise a week. Researchers also found that sedentary muscle contained about half as much of a key protein needed to convert sugar into usable energy.
The protein, MPC1, transports a key byproduct of sugar breakdown into the mitochondria.
The study, published Friday in Clinical Bioenergetics, examined nine sedentary and 10 regularly active men, approximately 42-years-old. A companion study on women is currently being planned. Researchers analyzed muscle biopsies to observe how efficiently the mitochondria burned fuel and performed exercise tests to measure fitness, fat-burning capacity and blood lactate levels — a key marker of how hard the body has to work for energy.
When compared to the active group, sedentary men showed significant cellular deficits:
- Mitochondrial Efficiency: Dropped by 28% to 36% across several categories.
- Fuel Transport: The MPC1 protein was 49% lower, reducing the muscle's ability to burn sugar. Similarly, the CPT1 enzyme, which transports fats into the mitochondria, was roughly half as active.
- Cardiovascular & Blood Markers: Sedentary men had a 38% lower maximal oxygen use (VO2max) and accumulated 60% higher levels of lactate in their blood during exertion.
San Millan said this represents a fundamental shift in cellular identity. Sedentary people aren't just "out of shape" — their cells are losing the ability to process fuel efficiently. For example, the massive drop in MPC1 could be one of the earliest signs of the cellular traffic jams that eventually cause insulin resistance and type 2 diabetes.
San Millan, a renowned physiologist known for his work in elite sports performance, including with Tour de France champion Tadej Pogačar, noted that the study highlights how regular exercise acts as a literal shield for cellular health, helping mitochondria seamlessly switch between burning fat and carbohydrates, a term that is called metabolic flexibility.
“Being sedentary will progressively erode metabolic health. When you stop moving, you lose that cellular identity of being healthy, and your body begins moving toward disease,” San Millan said.
The research team hopes to conduct larger, more diverse trials in the future and run training or drug trials to see if MPC1 and CPT1 can recover with intervention.
“This cellular decline is something we can actually test for in a non-invasive way, through cardiopulmonary exercise testing and lactate testing,” San Millan said. “And if we catch it early, we can prescribe targeted exercise programs designed to restore mitochondrial health and potentially prevent future disease.”
The study co-authors include Janel L. Martinez, Genevieve C. Sparagna, Angelo D’Alessandro, Davide Stefanoni, Travis Nemkov and John Hill.