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.