Impaired protein quality control system underlies mitochondrial dysfunction in skeletal muscle of streptozotocin-induced diabetic rats

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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.

Graphical abstract

Highlights

► After 4 months of STZ administration gastrocnemius IMF mitochondria functionality decreased. ► Increased mitochondria carbonylation levels were paralleled by decreased OXPHOS activity. ► Decreased mitochondria proteolysis was related with increased protein oxidation. ► AAA proteases activity and expression decreased in diabetic animals.

Abbreviations

BN-PAGE
blue native polyacrylamide gel electrophoresis
Anti-DNP
anti-2,4-dinitrophenylhydrazone
OXPHOS
oxidative phosphorylation
IMF
intermyofibrillar mitochondria
STZ
streptozotocin
T1DM
type 1 diabetes mellitus

Keywords

Intermyofibrillar mitochondria
Mitochondrial proteolysis
Protein quality control
Gastrocnemius
Type 1 diabetes mellitus

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