title: 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.
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Allwood
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Foster
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Arkell
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Marie-Soleil
authors.initials: MS
authors.lastname: Beaudoin
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Laelie A
authors.initials: LA
authors.lastname: Snook
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Nadya
authors.initials: N
authors.lastname: Romanova
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Coral L
authors.initials: CL
authors.lastname: Murrant
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Holloway
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada.
authors.forename: David C
authors.initials: DC
authors.lastname: Wright
authors.affiliation: Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada jeremys@uoguelph.ca.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Simpson
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D006439:Hemodynamics; D007333:Insulin Resistance; D008297:Male; D018908:Muscle Weakness / Q000473:pathology / Q000503:physiopathology*; D055435:Myostatin / Q000378:metabolism; D009765:Obesity / Q000503:physiopathology; D051381:Rats; D011924:Rats, Zucker; D012132:Respiratory Muscles / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D055435:Myostatin; D051899:Smad2 Protein; C497784:Smad2 protein, rat
keywords: adipocyte; diabetes; diaphragm; myostatin; obesity