Abstract
Maple Syrup Urine Disease (MSUD) is an inherited disorder caused by the dysfunction in the branched chain keto-acid dehydrogenase (BCKDH) enzyme. This leads to buildup of branched-chain keto-acids (BCKA) and branched-chain amino acids (BCAA) in body fluids (e.g. keto-isocaproic acid from the BCAA leucine), leading to numerous clinical features including a less understood skeletal muscle dysfunction in patients. KIC is an inhibitor of mitochondrial function at disease relevant concentrations. A murine model of intermediate MSUD (iMSUD) shows significant skeletal muscle dysfunction as by judged decreased muscle fiber diameter. MSUD is an orphan disease with a need for novel drug interventions. Here using a 96-well plate (liquid chromatography- mass spectrometry (LC-MS) based drug-screening platform we show that Metformin, a widely used anti-diabetic drug, reduces levels of KIC in patient-derived fibroblasts by 20–50%. This Metformin-mediated effect was conserved in vivo; Metformin-treatment significantly reduced levels of KIC in the muscle (by 69%) and serum (by 56%) isolated from iMSUD mice, and restored levels of mitochondrial metabolites (e.g. AMP and other TCA). The drug also decreased the expression of mitochondrial branched chain amino transferase (BCAT) which produces KIC in skeletal muscle. This suggests that Metformin can restore skeletal muscle homeostasis in MSUD by decreasing mitochondrial KIC production.
Highlights
Maple Syrup Urine Disease (MSUD) is an inherited disorder in branched-chain amino acid (BCAA) catabolism caused by mutations in genes that encode the components of the branched chain keto-acid dehydrogenase (BCKDH) complex, which catalyzes the first irreversible step in BCAA catabolism[1,2,3]
To determine whether the intermediate MSUD (iMSUD) mouse model had muscle fiber defects similar to that observed in patients with MSUD, quadriceps and gastrocnemius muscles were isolated from iMSUD mice and compared to wild-type littermate controls. iMSUD mice displayed a significant reduction in muscle fiber size, suggesting muscle atrophy (Fig. 1c)
ketoisocaproic acid (KIC) and its’ corresponding branched-chain amino acid (BCAA) precursor, leucine are the major toxic metabolites associated with MSUD related symptoms[20], we focused on KIC metabolism in this study
Summary
Chain Amino Acid (BCAA) derived ketoacidosis and promotes received: 04 March 2016 accepted: 08 June 2016 Published: 04 July 2016 metabolic homeostasis in MSUD. MRNA levels (Fig. 1g) of mitochondrial genes (cytochrome c oxidase subunit II (COX II), adenine nucleotide translocase-1 (ANT1), and mitochondrial transcription factor A (TFAM)) were significantly decreased in iMSUD mice compared to wild-type It is well-known that pathways related to oxidative stress-response are activated by mitochondrial dysfunction in skeletal muscle[28]. These findings suggest a mitochondria-specific role for Metformin in modulating BCAA catabolism This effect was conserved in vivo, as judged by measuring the expression of skeletal muscle BCAT-1 and 2 in iMSUD mice treated with Metformin for 4 days (Figs 3c and S3). MRNA levels of mitochondrial BCAT-2 (Fig. 3c) but not cytoplasmic BCAT-1 (Figure S4) were significantly decreased in mice treated with Metformin, suggesting that BCAT-2 is a relevant target of Metformin both in vitro and in vivo. The wide-spread and safe use of Metformin for treating diabetes, suggests that translational studies can be readily carried out for repurposing this drug for long-term management of MSUD in conjunction with currently used dietary interventions
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