Myostatin‐dependent detrusor remodelling mediates contractility impairment in diabetic rats’ bladder – a maximal elastance analysis

The role of myostatin, an endogenous myokine mediating the pathological progression of myopathy, in contractility impairments of the chronically diabetic bladder remains unclear. This study examined whether maximal elastance (mE) reliably and validly assesses bladder contractility in vivo and investigated the role of myostatin-associated tissue remodelling in the contractility deficits in diabetic bladder. Eighty-three female Sprague-Dawley rats were assigned to control (CON), streptozotocin-treated (STZ; 30 mg/kg twice, i.p.) and STZ with non-specific IgG (STZ + IgG; 2 mg/kg, i.p.) or Myo-029 (a myostatin-neutralizing antibody; STZ + MYO; 2 mg/kg, i.p.). The slope of the end-emission pressure-volume relationship obtained from pressure-volume analysis was calculated as mE. mE remained relatively constant under altered preload and afterload but increased dose dependently with muscarine infusion (10 and 100 µM, 0.002 mL/min, i.a.) and decreased with atropine infusion (10 and 100 µM, 0.002 mL/min, i.a.). Compared to CON the STZ group showed decreased mE, reduced muscle-to-collagen ratio, increased myostatin expression, decreased myosin heavy chain 11 (MHC 11) and smoothelin expressions, as well as upregulated α-smooth muscle actin (SMA) and collagen type I alpha 1 (COL1A1) expressions. Treatment with Myo-029 in STZ animals reversed the reductions in the MHC 11 and smoothelin expressions, muscle-to-collagen ratio and mE, as well as the STZ-upregulated SMA and COL1A1 expression. Collectively mE effectively assessed bladder contractility in vivo. Moreover myostatin contributes to diabetes-associated deficits in bladder contractility by regulating detrusor remodelling, suggesting that myostatin may represent a potential therapeutic target for diabetes-associated cystopathy. KEY POINTS: Developing a methodology capable of precisely assessing bladder contractility in vivo is warranted to elucidate the underlying pathophysiology of bladder contractility impairments. The pathological progression of diabetic cystopathy has been linked to myogenic dysfunction of the detrusor, resulting in impaired bladder contractility. Maximal elastance (mE) is a bladder contractility-sensitive parameter that is independent of bladder preload and afterload. Bladders from long-standing diabetic rats exhibit diminished contractility, accompanied by upregulation of myostatin and downregulation of myosin heavy chain 11 and smoothelin. Administration of a myostatin-specific neutralizing antibody in diabetic rats reversed diabetes-associated downregulation of myosin heavy chain 11 and smoothelin, as well as bladder contractility impairment. mE effectively assessed bladder contractility in vivo. Moreover myostatin contributes to diabetes-associated deficits in bladder contractility by regulating myostatin-dependent detrusor remodelling, suggesting that myostatin may represent a potential therapeutic target for diabetic cystopathy.