Combined effects of a ketogenic diet and exercise training alter mitochondrial and peroxisomal substrate oxidative capacity in skeletal muscle

Abstract

Ketogenic diets (KD) are reported to improve body weight, fat mass, and exercise performance in humans. Unfortunately, most rodent studies have used a low-protein KD, which does not recapitulate diets used by humans. Since skeletal muscle plays a critical role in responding to macronutrient perturbations induced by diet and exercise, the purpose of this study was to test if a normal-protein KD (NPKD) impacts shifts in skeletal muscle substrate oxidative capacity in response to exercise training (ExTr). A high fat, carbohydrate-deficient NPKD (16.1% protein, 83.9% fat, 0% carbohydrate) was given to C57BL/6J male mice for 6 weeks, while controls received a low fat diet with similar protein (15.9% protein, 11.9% fat, 72.2% carbohydrate). On week four of the diet, mice began treadmill training 5 days/week, 60 min/day for 3 weeks. NPKD-fed mice increased body weight and fat mass, while ExTr negated a continued rise in adiposity. ExTr increased intramuscular glycogen, while the NPKD increased intramuscular triglycerides. Neither the NPKD nor ExTr alone altered mitochondrial content; however, in combination, the NPKD-ExTr group showed increases in PGC-1α, as well as markers of mitochondrial fission and fusion. Pyruvate oxidative capacity was unchanged by either intervention, while ExTr increased leucine oxidation in NPKD-fed mice. Lipid metabolism pathways had the most notable changes as the NPKD and ExTr interventions both enhanced mitochondrial and peroxisomal lipid oxidation and many adaptations were additive or synergistic. Overall these results suggest a combination of a NPKD and ExTr induces additive and/or synergistic adaptations in skeletal muscle oxidative capacity.

The Overlooked Transformation Mechanisms of VLCFAs: Peroxisomal β-Oxidation

“…They found that overexpression of PGC-1α induced the expression of AOCX1, and that the levels of some proteins associated with peroxisome activity also substantially increased [87]. In addition, some studies have also demonstrated the importance of PGC-1α in peroxisomes [88,89].…”

The impact of diet upon mitochondrial physiology (Review)

“…The majority of studies conducted on rodents have used a low-protein KD. As such, recently, Huang et al ( 143 ) investigated the possible alterations of a normal-protein KD (NPKD) upon the substrate oxidative capacity in the skeletal muscle of C57BL/6 male mice which were also introduced to an exercise training regime. The application of NPKD or exercise training alone could not produce changes in the mitochondrial content, while their combined application was found to increase both mitochondrial fission/fusion markers and PGC-1α levels.…”

Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives

“…The favorable changes in body composition from KDs appear to be influenced by the degree of nutritional ketosis achieved [ 85 ]. KDs may exert a protective effect against muscle mass loss, potentially through maintenance rather than a net hypertrophic effect [ 84 ].…”

“…CR facilitates mitochondrial fat oxidation in SKM through upregulated AMPK signaling, working in opposition to IGF-1-mediated activation of mTOR [ 111 ]. KDs may contribute to SKM maintenance or growth through upregulation of mTOR signaling [ 85 , 112 ]. Huang et al showed that a normal-protein KD activated mTOR-related proteins that drive protein synthesis over autophagy [ 85 ].…”

“…KDs may contribute to SKM maintenance or growth through upregulation of mTOR signaling [ 85 , 112 ]. Huang et al showed that a normal-protein KD activated mTOR-related proteins that drive protein synthesis over autophagy [ 85 ]. In addition, Roberts et al showed that, in aged mice, a KD preserved muscle mass and motor function by increasing protein acetylation levels and modulating mTORC1 signaling in a tissue-dependent manner [ 113 ].…”