Helen Blau, PhD, Professor, Department of Microbiology and Immunology–Baxter Labs, Stanford University

Research Description: The Blau lab has discovered that prostaglandin E2 (PGE2), a crucial lipid metabolite involved in the body's natural inflammatory healing response, plays a vital role in supporting skeletal muscle growth after injury. We recently published a study showing that genetic ablation of the PGE2 receptor EP4 from skeletal muscle stem cells results in impaired muscle regeneration. Additionally, using ibuprofen to reduce PGE2 production by inhibiting COX-2 activity, a key enzyme in the synthesis of PGE2, also hampered muscle regeneration in experimental models. The Blau lab has also demonstrated that 15-PGDH (15-prostaglandin dehydrogenase), the enzyme responsible for PGE2 degradation, increases in muscle with aging, and plays a pivotal role in aging-associated muscle atrophy. Pharmacological inhibition of 15-PGDH by a small molecule inhibitor in geriatric mice increased muscle strength and rejuvenated the muscle tissue. Conversely, overexpression of 15-PGDH in young mice induces muscle weakness and atrophy thus underlying the detrimental involvement of this novel regulator of muscle mass, 15-PGDH. Obesity is known to trigger a cascade of inflammatory responses within the body, much like sarcopenia, a condition characterized by the loss of muscle mass and strength. A recent investigation employing a mouse model subjected to a high-fat diet, a common method to induce obesity, was applied to study the impact on muscle health6 . Remarkably, the findings reproduced observations in human subjects that Semaglutide administration led to reductions in muscle mass and strength, not just fat mass. The similar inflammatory environment of obesity to sarcopenia, a condition that inhibition of 15-PGDH activity has shown to mitigate in mice, suggests the potential efficacy of inhibiting 15-PGDH as a therapeutic strategy to mitigate muscle wasting associated with managing obesity using GLP-1 agonists. Our project goals are 1) To determine the effects of Semaglutide-induced loss of muscle mass and force. 2) To determine if the 15-PGDH inhibition mitigates the muscle loss induced by Semaglutide treatment. 3) To investigate the mechanism of Semaglutide treatment together with 15-PGDH inhibition (a) directly on muscle fiber hypertrophy or (b) following muscle injury as occurs with exercise. Dr. Blau serves on the Stanford NORC Internal Advisory Committee (IAC) and collaborates extensively with NORC members, including Dr. J. Wu.