Augmented Muscle Mass as a Novel Buffer against Obesity‐Derived Hypertension

Obesity is well known to significantly compromise cardiovascular and metabolic function and a front line intervention for the management of obesity is exercise, which reduces adverse cardiovascular related outcomes by increasing weight loss and augmenting muscle mass. Myostatin is a potent negative regulator of skeletal muscle shown to be upregulated in human and animal models of obesity, thus making myostatin an intriguing target for therapeutic intervention, particularly in patients who cannot undergo extensive lifestyle modifications due to various comorbidities. The model used was the db/db mouse, a well characterized mimic of the human condition of obesity, in combination with myostatin deletion. The study used four groups of mice, lean control, lean myostatin KO, obese control, obese myostatin KO. The current study found that augmented muscle mass, through myostatin deletion, prevents hypertension in the db/db mouse. Blood pressure (measured using radiotelemetry in conscious freely moving animals) between the lean and lean KO mice was similar (108 ± 1.5 vs. 105 ± 2.1 mmHg) but obese mice have significantly elevated blood pressure compared to obese KO (117 ± 1.6 vs. 108 ± 2.1 mmHg, p < 0.05). The obese groups have similar mass, fat profiles (NMR), activity (CLAMS) and heart rate, thus the improved cardiovascular outcomes occur despite full presentation of the classic db/db phenotype, indicating that the positive cardiovascular benefits conferred from augmented muscle mass are independent of weight loss. Further studies in lean mice have shown that myostatin deletion significantly delays the onset of hypertension with Angiotensin 2 infusion (800 ug/kg/min). This study also presents the novel finding that deletion of myostatin is accompanied by significant improvement in renal fluid dynamics, both in the lean and obese groups. The lean KO mice have significantly increased urine sodium concentration compared to lean control (197.9 ± 16.4 vs. 155 ± 13.7 mM, p < 0.05) and the obese KO also is significantly increased compared to the obese control (130 ± 7.9 vs. 62 ± 28.58 mM, p < 0.05), Importantly urine micro‐albuminuria, a clinically relevant measure of kidney function assessed by the albumin to creatinine ratio, remains similar in the lean and lean KO (328 ± 85.9 vs. 126 ± 29.3 ug/mg/day) but is rescued in the obese KO compared to obese control (315 ± 77.6 vs. 1037 ± 219.1 ug/mg/day, p < 0.05). Together, these experimental observations suggest that myostatin inhibition could serve as an effective target for conferring the protective cardiovascular benefits of augmented muscle mass (independent of exercise) and prevent/reverse obesity‐derived changes to metabolic, renal and cardiovascular function. Support or Funding Information Stepp and Fulton NHLBI RO1 HL124773