An Exercise Mimetic Blunts Influenza‐Induced Mortality in Middle Aged and Obese Mice

Abstract

Viral infection is well known for its ability to significantly compromise cardiovascular health, and elevate morbidity and mortality in healthy (and unhealthy) patients. Susceptibility to the consequences of viral infection are significantly elevated in the obese and aged populations. Even modest amounts of exercise are protective against influenza, influenza severity and mortality, and additionally enhance immunization efficacy in both human and rodent models. However, exercise is contra‐indicated in those with viral infection, due to potential contagiousness and a weakened immune state. Further, a significant patient population is unable to exercise at a rate that confers cardiovascular benefit (ex: the aged, obese, those constrained by a pandemic). Thus, it would be inherently valuable to determine if an exercise mimetic can protect and preserve function, independent of increases in activity or exercise. To address this question, our lab manipulates the muscle myokine myostatin (GDF‐8) in obese and aged mouse models. Myostatin is a potent negative regulator of skeletal muscle growth that is upregulated in human and animal models of obesity, influenza, and downregulated following regular exercise. Our hypothesis is that targeting myostatin in a rodent model of influenza will prevent mortality via a mechanism that mimics the benefits of exercise.Influenza infection was induced via intranasal administration of Influenza A/PR/8/34 in WT and obese (db/db) mice with and without myostatin deletion. Importantly, middle aged mice (aged 40‐60 wks) were used to appropriately mimic a susceptible human phenotype. Assessed variables included weight, survival, coat score and inflammatory factors in the lung.Myostatin deletion significantly improved survival in mice compared to infected controls, with lean controls experiencing ~27% mortality and obese controls experiencing ~50% mortality. No mortality was observed in obese and lean groups with myostatin deleted. All groups experienced similar weight loss, demonstrating effective influenza infection. Lung inflammatory factors showed significantly elevated IL‐2, MCP‐1, and IL1b in infected lean myostatin KO mice, as well as NOX1 and NOX2, compared to infected controls. Taken together, our data suggests that myostatin may be an effective target for improving outcomes in influenza infection.