Respiratory muscle weakness in the Zucker diabetic fatty rat

Abstract

The obesity epidemic is considered one of the most serious public health problems of the modern world. Physical therapy is the most accessible form of treatment; however, compliance is a major obstacle due to exercise intolerance and dyspnea. Respiratory muscle atrophy is a cause of dyspnea, yet little is known of obesity-induced respiratory muscle dysfunction. Our objective was to investigate whether obesity-induced skeletal muscle wasting occurs in the diaphragm, the main skeletal muscle involved in inspiration, using the Zucker diabetic fatty (ZDF) rat. After 14 wk, ZDF rats developed obesity, hyperglycemia, and insulin resistance, compared with lean controls. Hemodynamic analysis revealed ZDF rats have impaired cardiac relaxation (P = 0.001) with elevated end-diastolic pressure (P = 0.006), indicative of diastolic dysfunction. Assessment of diaphragm function revealed weakness (P = 0.0296) in the absence of intrinsic muscle impairment in ZDF rats. Diaphragm morphology revealed increased fibrosis (P < 0.0001), atrophy (P < 0.0001), and reduced myosin heavy-chain content (P < 0.001), compared with lean controls. These changes are accompanied by activation of the myostatin signaling pathway with increased serum myostatin (P = 0.017), increased gene expression (P = 0.030) in the diaphragm and retroperitoneal adipose (P = 0.033), and increased SMAD2 phosphorylation in the diaphragm (P = 0.048). Here, we have confirmed the presence of respiratory muscle atrophy and weakness in an obese, diabetic model. We have also identified a pathological role for myostatin signaling in obesity, with systemic contributions from the adipose tissue, a nonskeletal muscle source. These findings have significant implications for future treatment strategies of exercise intolerance in an obese, diabetic population.

Fibro-Adipogenic Remodeling of the Diaphragm in Obesity-Associated Respiratory Dysfunction

“…Preclinical studies of respiratory function in obesity have largely employed genetically obese Zucker diabetic fatty (ZDF) rats. In this model, ex vivo diaphragmatic testing has yielded equivocal results, with contractile force reduced in older animals (8) but unchanged (9,10) or increased (11) in younger animals. ob/ob mice demonstrate hypoventilation reversible by leptin infusion, indicating that this adipokine may regulate central respiratory drive (12).…”

Increased Fibro-Adipogenic Progenitors and Intramyocellular Lipid Accumulation in Obesity-Related Skeletal Muscle Dysfunction

“…To this point, the diaphragm is the primary skeletal muscle for supporting gas exchange and normal respiratory function. Recent data indicate that diaphragm skeletal muscle wasting is involved in inspiration dysfunction in the Zucker diabetic fatty rat (12). In their study in this issue of Diabetes , Buras et al (13) further investigated whether fibro-adipogenic diaphragm remodeling occurs in obesity-associated respiratory impairment and whether FAPs contribute to skeletal muscle dysfunction in a clinically relevant mouse model of high-fat diet–induced obesity and associated respiratory dysfunction.…”

Protective effect of exogenous hydrogen sulfide on diaphragm muscle fibrosis in streptozotocin-induced diabetic rats

“…4 The diaphragm is an important skeletal muscle involved in respiration in mammals. 5 A previous study by our group reported that diaphragmatic contractile function significantly declined in streptozotocin (STZ)-induced diabetic rats, and that the mechanism was correlated with excessive oxidative stress and inflammation in diaphragmatic tissue. 6 Moreover, the excessive inflammatory reaction in diabetes often causes collagen deposition and muscle fibrosis.…”