Obesity and aging have both seen dramatic increases in prevalence throughout society. This review seeks to highlight common pathologies that present with obesity, along with the underlying risk factors, that have remarkable similarity to what is observed in the aged. These include skeletal muscle dysfunction (loss of quantity and quality), significant increases in adiposity, systemic alterations to autonomic dysfunction, reduction in nitric oxide bioavailability, increases in oxidant stress and inflammation, dysregulation of glucose homeostasis, and mitochondrial dysfunction. This review is organized by the aforementioned indices and succinctly highlights literature that demonstrates similarities between the aged and obese phenotypes in both human and animal models. As aging is an inevitability and obesity prevalence is unlikely to significantly decrease in the near future, these two phenotypes will ultimately combine as a multidimensional syndrome (a pathology termed sarcopenic obesity). Whether the pre-mature aging indices accompanying obesity are additive or synergistic upon entering aging is not yet well defined, but the goal of this review is to illustrate the potential consequences of a double aged phenotype in sarcopenic obesity. Clinically, the modifiable risk factors could be targeted specifically in obesity to allow for increased health span in the aged and sarcopenic obese populations.

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.

Diabetes currently afflicts 34.2 million Americans, and approximately 1 in 3 are prediabetic (CDC, 2020). Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia due to the combination of insulin resistance and insufficient insulin production. Unfortunately, the reoccurring hyperglycemia in association with long‐term insulin malfunction has been tied to damage or failure of differing organs such as kidney, nerves, and vasculature (American Diabetes Association, 2007). The renal dysfunction caused by the hyperglycemia is the causative agent of two prominent clinical signs of T2D, polydipsia and polyuria. The most substantial predispositions for T2D are obesity, poor nutrition, sedentary lifestyle, and aging, which all negatively effects an individual’s skeletal muscle mass as well. Skeletal muscle is considered the largest metabolic reservoir due to its role as a glucose sink. Skeletal muscle can be categorized into oxidative and glycolytic fibers; however, oxidative fibers are more insulin sensitive and resistant to fatigue. Peroxisome proliferator‐activated receptor gamma coactivator 1 alpha (PGC1α) is an endogenous protein and potent activator of multiple metabolic pathways including: mitochondrial biogenesis, liver gluconeogenesis, oxidative muscle fibers, and blood glucose absorption and handling. Overexpression of PGC1α is known to increase insulin‐sensitive oxidative muscle fibers, but what remains unknown is whether it is effective at preventing cardiometabolic disease and skeletal muscle dysfunction in a mouse model of T2D. Our hypothesis is that overexpression of PGC1α will improve muscle performance by preventing fatigability, will preserve glucose homeostasis, and protect against kidney function in a mouse model of T2D. The T2D mouse model utilized was the db/db mouse, which possesses a dysfunctional leptin receptor and thus is chronically hyperphagic. By 12 weeks of age, it is well characterized as a model of Type 2 diabetes. Overexpression of PGC1a was obtained by crossing the MCK‐PGC1alpha transgenic mice onto the db/db background. Adult mice were used for the duration of the experiments with a total of four mouse groups; a lean control, a lean PGC1α overexpression, an obese control, and an obese PGC1α overexpression mouse. Multiple variables were assessed including glucose homeostasis (plasma glucose, HbA1c, IGTT), muscle function (in vivo plantarflexion of gastrocnemius muscle), and fluid dynamics (via metabolic cages). Overexpression of PGC1α improves glucose homeostasis, decreases muscle fatigability, and conserves fluid dynamics in a T2D mouse model. Furthermore, the overexpression of PGC1α returns the blood glucose levels and renal function in the T2D models back to levels of the controls, restoring them to a normal physiological state. Muscle rate of fatigue was significantly decreased in both the lean and obese mice, providing superior performance against fatigability. Altogether, this data suggests that targeting PGC1α is a possible intervention for T2D and potentially ...

Chronic Kidney Disease (CKD) afflicts ~15% of U.S. adults and occurs when the kidneys are ineffective in filtering the blood of waste products. CKD is irreversible and current interventions are focused on protecting and preserving renal function. Risk factors for CKD are multifactorial but growing evidence suggest that a key risk factor is dietary salt intake. A diet high in sodium will increase fluid retention, blood pressure, proteinuria, and ultimately drive the progression of kidney damage. Currently, it is estimated that 90% of the U.S. population consumes excess dietary sodium. As such, it is a medical necessity that interventions focus on ways to optimize renal sodium excretion and protect kidney function over time. Exercise is a key therapy to improve kidney function but a large amount of people are unable to exercise due to disability, lack of time or money, or a pandemic. Our lab has previously discovered that when myostatin, a negative regulator of skeletal muscle mass, is deleted from lean mice it also improves kidney function in diabetes. However, it is unknown whether myostatin deletion will also improve renal sodium handling. Thus, the hypothesis is that myostatin deletion improves sodium handling and protects against renal damage during a high salt diet. The experiment used adult lean mice with and without myostatin constitutively deleted. Both groups of mice were placed on a high salt (HS) diet (4% NaCl) for 14 days. Food consumption, water intake, and urine production was assessed at baseline, acutely (first 3 days on HS diet) and at the end of the experiment using metabolic cages. Blood pressure studies (in vivo) are ongoing and markers of renal (dys)function are currently being assessed, along plasma hormones that regulate fluid balance. Significance was determined at P<0.05. The results showed that myostatin deletion protects against kidney dysfunction during a high salt diet, as the myostatin KO mice consumed significantly more food, but maintained fluid balance (drank and urinated similar amounts to the lean control). Blood pressure remained lower in the myostatin KO compared to control. Importantly, myostatin deletion significantly blunted renal hypertrophy (68% less mass) compared to the control. Taken together, myostatin deletion improves the efficiency of the kidney in handling sodium and maintains fluid balance during a high salt diet. Thus, pharmaceutical inhibition of myostatin may prove an effective target for long‐term protection against high salt diets and preserving kidney function during CKD.

Type 1 Diabetes Mellitus (T1DM) is a disease characterized by the destruction of insulin‐secreting pancreatic beta cells and results in hyperglycemia, muscle wasting, and vascular dysfunction. Patients afflicted with T1DM suffer from increased morbidity and early mortality, largely driven by an inability to appropriately maintain glucose homeostasis. Skeletal muscle is the body’s largest metabolic reservoir, absorbing significant amounts of glucose from the bloodstream. The myokine myostatin is a potent negative regulator of muscle growth and is upregulated in T1DM patients but downregulated following regular exercise. Physical exercise is also known to improve cardiovascular health and increase insulin sensitivity of muscle, but many T1DM patients are unable to exercise at a level that conveys benefit due to muscle atrophy. Thus, directly targeting skeletal muscle, independent of exercise, may prove beneficial for T1DM therapy. Our hypothesis is that genetic deletion of myostatin will preserve glucose homeostasis, maintain muscle function, and protect against vascular dysfunction and cardiometabolic effects in a mouse model of T1DM. T1DM was induced via streptozotocin (STZ) in adult male mice with (WT) and without myostatin (MyoKO). Multiple variables were assessed including glucose homeostasis (plasma glucose, HbA1c, IGTT), fluid dynamics, muscle function (in vivo plantarflexion), and vascular function (ex vivo pressure myography of gracilis arteriole). Myostatin deletion inhibited STZ‐induced increases in plasma glucose, preserved fluid dynamics, and prevented decreases in muscle function, independent of insulin. Further, endothelial function was protected with myostatin deletion. Taken together, this data suggests that myostatin inhibition may be a target for effective treatment and management of the cardiometabolic and skeletal muscle dysfunction that occurs with T1DM.