Skeletal Muscle Gene Expression In Elite Ultra-endurance Athletes Habitually Consuming Very Low-carbohydrate or High-carbohydrate Diets

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A growing number of elite-level ultra-endurance athletes have switched from a high-carbohydrate (HCD) to a very low-carbohydrate/high-fat diet (LCD). LCD athletes exhibit greater than two-fold higher rates of peak fat oxidation compared to their high-carbohydrate counterparts. PURPOSE: In order to determine if the fat-adapted metabolic phenotype was associated with differences in skeletal muscle gene expression, we performed genome wide transcriptomic analysis in athletes who had been habitually consuming a LCD for a minimum of six months. METHODS: 20 elite ultra-endurance athletes (men, age 33.5 ± 6.4 yr, BMI 22.6 ± 3.3 kg/m2, VO2max 64.5 ± 4.9 mL/kg/min) habitually consuming a HCD (n=10; 58% CHO, 15% PRO, 28% FAT) or a LCD (n=10; 11% CHO, 19% PRO, 71% FAT) were matched for age, competition events, and performance. Muscle biopsies from the vastus lateralis were obtained in a fasted state. cDNA library was prepared from total RNA and sequenced for transcriptome expression using the Illumina HiSeq2500. Reads per kilobase of transcripts per million analysis was used to compare gene expression between groups (p ≤ 0.01) and with absolute fold changes (±2). RESULTS: Fat-adapted athletes had an average of 20 months (range 9-36 mo) on a LCD. Of the 25,262 total genes sequenced, 633 showed dietary differences (p ≤ 0.01). Sixty genes had greater than a 2-fold magnitude change including 47 upregulated (p ≤ 0.01) and 13 downregulated (p ≤ 0.01) genes. In the LCD athletes, two of the most significant upregulated genes coded for protein phosphatase 1 regulatory subunit 1A (+2.2 fold), an inhibitor of glycogen metabolism, and 3-hydroxy-3-methylglutaryl-CoA synthase 2 (+19.6 fold), an enzyme in ketogensis. The most significant downregulated gene coded for cAMP-specific 3’,5’-cyclic phosphodiesterase 4C, a key regulator of cAMP. CONCLUSION: Athletes habitually following a ketogenic diet showed distinct gene expression patterns that may give insight into the molecular mechanisms that mediate the fat-adapted phenotype.