Myostatin Deletion Prevents Kidney Specific Increases in NOX4 in Obesity and Protects Against Renal Injury and Hypertension
Authors: Butcher Joshua T. , Larion Sebastian , Mintz James D. , Fulton David J. , Stepp David W. 
Published: June 2021

Obesity is well characterized for its ability to compromise cardiometabolic function; being highly associated with hypertension and chronic kidney disease. Myostatin is a myokine, a cytokine–like factor that regulates muscle function and growth, which is a potent negative regulator of skeletal muscle growth and has been shown to be upregulated in obesity. NADPH oxidase 4 (NOX4) is known to play a key role in kidney function in diabetic nephropathy. However, while myostatin deletion has been shown to improve endothelial dysfunction in obesity, research has not been translated into a functional outcome (ie. blood pressure, kidney function, role of renal NOX4). The purpose of this study was to examine the effect of myostatin deletion on blood pressure regulation and kidney function in obesity.

The model used was the db/db mouse, a well characterized mimic of the human condition of obesity, in combination with constitutive myostatin deletion. Kidney function was assessed using metabolic cages and urine analyzed for electrolyte concentration and micro‐albumin excretion. Blood pressure was quantified using in vivo radiotelemetry.

The current study found that myostatin deletion improves renal injury and prevents hypertension in the db/db mouse. Microalbumin excretion, a measure of renal injury, was significantly elevated in obesity compared to lean mice (892.5 ± 180.1 vs. 230.9 ± 63.7 ug/day, p < 0.05) and significantly improved with myostatin deletion (200.2 ± 49.1 ug/day). Blood pressure was elevated with obesity compared to lean control (117.5 ± 1.2 vs. 107.8 ± 1.5 mmHg, p < 0.05) and significantly improved with myostatin deletion (108.4 ± 1.8 mmHg). Further, the significant polydipsia (excessive thirst) and polyuria (excess urination) that accompanies obesity is improved with deletion of myostatin. The improved renal dynamics observed with myostatin deletion were accompanied with an ability of the kidney to concentrate sodium compared to the obese control (105.1 ± 11.2 vs. 53.2 ± 8.0 mM, p < 0.05), resulting in a more efficient kidney. Important confounding variables were identified and found to be unchanged in obesity (weight, fat profiles, activity, heart rate, and aldosterone) thus the improved cardiovascular outcomes occur despite full presentation of the classic db/db phenotype. Renal NOX4 mRNA was found to be significantly upregulated in obesity when normalized to lean mice (> 300 %) and rescued with myostatin deletion (~ 40 %). To conclude, myostatin deletion ameliorates kidney injury (and data suggests a novel role for NOX4), results in a more efficient kidney and rescues blood pressure in obesity. These experimental observations suggest that myostatin inhibition could serve as an effective target for prevention/reversal of obesity‐derived changes to renal and cardiovascular function.

Support or Funding Information

Research Support: Stepp and Fulton NHLBI R01 HL124773 and Butcher AHA 17POST33410322

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.