title: Impaired protein quality control system underlies mitochondrial dysfunction in skeletal muscle of streptozotocin-induced diabetic rats.
abstract: Hyperglycaemia-related mitochondrial impairment is suggested as a contributor to skeletal muscle dysfunction. Aiming a better understanding of the molecular mechanisms that underlie mitochondrial dysfunction in type 1 diabetic skeletal muscle, the role of the protein quality control system in mitochondria functionality was studied in intermyofibrillar mitochondria that were isolated from gastrocnemius muscle of streptozotocin (STZ)-induced diabetic rats. Hyperglycaemic rats showed more mitochondria but with lower ATP production ability, which was related with increased carbonylated protein levels and lower mitochondrial proteolytic activity assessed by zymography. LC-MS/MS analysis of the zymogram bands with proteolytic activity allowed the identification of an AAA protease, Lon protease; the metalloproteases PreP, LAP-3 and MIP; and cathepsin D. The content and activity of the Lon protease was lower in the STZ animals, as well as the expression of the m-AAA protease paraplegin, evaluated by western blotting. Data indicated that in muscle from diabetic rats the mitochondrial protein quality control system was compromised, which was evidenced by the decreased activity of AAA proteases, and was accompanied by the accumulation of oxidatively modified proteins, thereby causing adverse effects on mitochondrial functionality.
authors.affiliation: QOPNA, Chemistry Department, University of Aveiro, Portugal.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Padrão
authors.forename: Tiago
authors.initials: T
authors.lastname: Carvalho
authors.forename: Rui
authors.initials: R
authors.lastname: Vitorino
authors.forename: Renato M P
authors.initials: RM
authors.lastname: Alves
authors.forename: Armando
authors.initials: A
authors.lastname: Caseiro
authors.forename: José Alberto
authors.initials: JA
authors.lastname: Duarte
authors.forename: Rita
authors.initials: R
authors.lastname: Ferreira
authors.forename: Francisco
authors.initials: F
authors.lastname: Amado
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010447:Peptide Hydrolases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D024101:Mitochondrial Proteins; D010447:Peptide Hydrolases