"The Silent Saboteur: How Developmental Arsenic Exposure Rewires Skeletal Muscle Energy Metabolism", Department of Environmental and Occupational Health, School of Public Health. 

Committee: 

• Aaron Barchowsky (advisor), EOH
• Wan-Yee Tang, EOH
• Nicholas Fitz, EOH
• Stacy Gelhaus, Department of Pharmacology and Chemical Biology, School of Medicine

Abstract: 

Skeletal muscle is far more than the engine that powers movement. It is a living reservoir of energy, continuously sensing, storing, and redistributing fuel to sustain the body’s metabolic needs. When this finely tuned system falters, the result is not only muscle weakness but a ripple of metabolic instability that can compromise overall health.

Arsenic, a naturally occurring element, has woven a dark thread through human history. Once called the “king of poisons”, it was both a medicine and a murder weapon, valued for its invisible power to heal or to kill. Centuries later, its shadow persists. Today, arsenic contaminates drinking water across the globe, quietly threatening the health of hundreds of millions. While its connections to cancer and diabetes are well established, its impact on skeletal muscle remains largely overlooked.

This dissertation investigates how developmental arsenic exposure reprograms skeletal muscle energy metabolism, producing long-term effects on muscle function and metabolic health. Integrated untargeted metabolomic and lipidomic analyses revealed suppression of glycolysis and the pentose phosphate pathway, consistent with reduced glucose utilization and impaired redox balance. Lipidomic profiling showed extensive remodeling of phospholipid and triglyceride species that were sex dependent. In males, elevated levels of specific phosphatidylcholine species point to changes in membrane composition that could influence membrane fluidity and mitochondrial integrity. In contrast, females showed a distinct lipid response with marked decreases and greater variability among triglyceride subclasses, suggesting disruptions in lipid storage and utilization.

Targeted biochemical studies in males confirmed an energetic deficit defined by glycogen depletion, lactate accumulation, and disrupted one-carbon metabolism. These results highlight glycogen homeostasis as a central vulnerability in arsenic-exposed muscle. Ongoing work is focused on examining both the synthesis and breakdown of glycogen through analyses of related enzymes and their activities to identify the drivers of this depletion. Additional efforts aim to explore how arsenic targets upstream regulators, including potential alterations in energy-sensing and redox-responsive signaling pathways such as AMPK and EGFR, to better understand how developmental arsenic exposure leads to profound energetic and molecular changes in skeletal muscle.

Together, these findings reveal skeletal muscle as a critical yet underappreciated target of arsenic toxicity. Developmental arsenic exposure rewires muscle metabolism, depleting glycogen reserves and impairing energy coordination, outcomes that may explain the fatigue and metabolic deficits observed in exposed populations. This work lays the foundation for understanding how a silent environmental stressor can leave a lasting molecular imprint on the body’s most energy-demanding tissue.