A ketogenic amino acid rich diet benefits mitochondrial homeostasis by altering the AKT/4EBP1 and autophagy signaling pathways in the gastrocnemius and soleus

• Published in: Biochimica et biophysica acta Vol. 1862; no. 7; pp. 1547 - 1555
• Main Authors: Li, Jinpeng, Kanasaki, Megumi, Xu, Ling, Kitada, Munehiro, Nagao, Kenji, Adachi, Yusuke, Jinzu, Hiroko, Noguchi, Yasushi, Kohno, Miyuki, Kanasaki, Keizo, Koya, Daisuke
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2018
• Subjects: AKT/4EBP1; Autophagy; Gastrocnemius and the soleus; High fat diet; Ketogenic amino acid; Mitochondrial fusion and fission; Ketogenic amino acid; AKT/4EBP1; Mitochondrial fusion and fission; Autophagy; Gastrocnemius and the soleus; High fat diet; autophagy; mitochondrial fusion and fission; gastrocnemius and the soleus; high fat diet
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2018.03.013

Muscle biology is important topic in diabetes research. We have reported that a diet with ketogenic amino acids rich replacement (KAAR) ameliorated high-fat diet (HFD)-induced hepatosteatosis via activation of the autophagy system. Here, we found that a KAAR ameliorated the mitochondrial morphological alterations and associated mitochondrial dysfunction induced by an HFD through induction of the AKT/4EBP1 and autophagy signaling pathways in both fast and slow muscles. The mice were fed with a standard HFD (30% fat in food) or an HFD with KAAR (HFDKAAR). In both the gastrocnemius and the soleus, HFDKAAR ameliorated HFD-impaired mitochondrial morphology and mitochondrial function, characterized by decreased mitofusin 2, optic atrophy 1, peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α and PPARα levels and increased dynamin-related protein 1 levels. The decreased levels of phosphorylated AKT and 4EBP1 in the gastrocnemius and soleus of HFD-fed mice were remediated by HFDKAAR. Furthermore, the HFDKAAR ameliorated the HFD-induced autophagy defects in the gastrocnemius and soleus. These findings suggest that KAAR may be a novel strategy to combat obesity-induced mitochondrial dysfunction, likely through induction of the AKT/4EBP1 and autophagy pathways in skeletal muscle. •KAAR ameliorated mitochondrial morphological alterations and associated mitochondrial dysfunction.•KAAR maintained the mitochondrial homeostasis through induction of AKT/4EBP1 and autophagy pathways in skeletal muscles.•KAAR ameliorated HFD-induced molecular defects in mitochondrial biogenesis.•The beneficial effect of KAAR on HFD-deteriorated mitochondrial health was comparable to that of exercise.