Myostatin Deletion Protects Against Renal Dysfunction During a High Salt Diet

Abstract

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.