Journal: Nature Communications

Article Title: A ketogenic diet enhances aerobic exercise adaptation and promotes muscle mitochondrial remodeling in hyperglycemic male mice

doi: 10.1038/s41467-026-69349-5

Figure Lengend Snippet: A Experimental timeline: 8-wk old male CD-1 mice were injected on two consecutive days with 40 mg/kg streptozotocin to induce hyperglycemia. Two weeks later, hyperglycemic mice were stratified to receive a typical high carbohydrate diet (CHOW), or a high-fat ketogenic diet (KETO). Eight-wks after diet induction, mice were stratified into static cages (Sedentary), or voluntary wheel running cages (Exercise Training). Original diets were maintained during the exercise-training period. Following 8-wks of exercise, blood and tissues were collected. [B] Body mass and [C] Blood glucose were measured weekly. For B , C : CON-CHOW n = 29, STZ-CHOW n = 30, STZ-KETO n = 29. D Glucose tolerance was impaired in both STZ-treated groups, E as demonstrated by higher glucose area under the curve ( p < 0.0001, CON-CHOW n = 29, STZ-CHOW n = 26, STZ-KETO n = 29). F Fasting insulin was ~50% lower in both STZ-treated groups, independent of dietary treatment, demonstrating that KETO reverses hyperglycemia independent of insulin levels (CON-CHOW n = 29, STZ-CHOW n = 30, STZ-KETO n = 30). G Blood ketones were significantly elevated in KETO compared to CHOW-fed groups ( p < 0.0001, CON-CHOW n = 27, STZ-CHOW n = 27, STZ-KETO n = 27). Data from ( B – G ) are presented as mean ± SEM. Data from ( E – G ) were analyzed by One-way ANOVA with Tukey post-hoc testing. Gray circles represent CON-CHOW, blue circles represent STZ-CHOW, and orange circles represent STZ-KETO. Source data are provided as a Source Data file. Figure ( A ) c reated in BioRender. Lessard, S. (2026) https://BioRender.com/cm7jtp4 .

Article Snippet: Blood ketones were measured using Precision Xtra Blood Glucose & Ketone Monitoring System (Abbott, 9881465).

Techniques: Injection

Journal: Nature Communications

Article Title: A ketogenic diet enhances aerobic exercise adaptation and promotes muscle mitochondrial remodeling in hyperglycemic male mice

doi: 10.1038/s41467-026-69349-5

Figure Lengend Snippet: A Daily running distance (CON-CHOW n = 13, STZ-CHOW n = 15, STZ-KETO n = 15), and B circadian running patterns were similar among groups (CON-CHOW n = 5, STZ-CHOW n = 7, STZ-KETO n = 7). C Training improved random blood glucose ( P = 0.0004, Sedentary: CON-CHOW n = 16; STZ-CHOW n = 15; STZ-KETO n = 15, Exercise-trained: CON-CHOW n = 13; STZ-CHOW n = 14; STZ-KETO n = 14) and D glucose tolerance ( P = 0.0004, Sedentary n = 12/group, Exercise-trained: CON-CHOW n = 11; STZ-CHOW n = 9; STZ-KETO n = 10) in all groups. E Blood ketones were decreased by training ( P = 0.0019), but still remained higher in STZ-KETO ( P < 0.0001, n = 8/group). F Body mass was higher in sedentary STZ-KETO ( P = 0.0176), but was reduced to the level of controls by exercise-training ( P < 0.0001). G Fat mass was higher in sedentary STZ-KETO, but was reduced to the level of controls with exercise-training ( P < 0.0001). H Percent lean mass was increased by exercise training in all groups ( P < 0.0001). For F – H Sedentary: CON-CHOW n = 15; STZ-CHOW n = 15; STZ-KETO n = 13, Exercise-trained: CON-CHOW n = 13; STZ-CHOW n = 14; STZ-KETO n = 13. Gray circles represent CON-CHOW, blue circles represent STZ-CHOW, and orange circles represent STZ-KETO. Data from ( A – H ) are presented as mean ± SEM. Panels C-H were analyzed by 2-way ANOVA with Tukey post-hoc testing. Source data are provided as a Source Data file.

Article Snippet: Blood ketones were measured using Precision Xtra Blood Glucose & Ketone Monitoring System (Abbott, 9881465).

Techniques:

Journal: Nature Communications

Article Title: A ketogenic diet enhances aerobic exercise adaptation and promotes muscle mitochondrial remodeling in hyperglycemic male mice

doi: 10.1038/s41467-026-69349-5

Figure Lengend Snippet: A Oxygen consumption expressed per lean mass (VO 2 /kg LM/min) was consistently higher in STZ-KETO during a 45 min bout of moderate intensity treadmill running exercise ( P < 0.0001). Data from the steady state (5–45 min) exercise period are shown. B Fat oxidation was calculated over the same acute exercise period, and showed a higher reliance on fatty acids as fuel during exercise in STZ-KETO ( P < 0.0001). C Respiratory exchange ratio (RER) was highest in STZ-CHOW and lowest in STZ-KETO during moderate intensity ( ~ 60% VO 2 peak) treadmill running ( P < 0.0001), indicating altered fuel metabolism (for ( A – C ): CON-CHOW n = 7, STZ-CHOW n = 8, STZ-KETO n = 7). Data from ( A – C ) are presented as mean ± SEM. Data were analyzed by 1-way ANOVA and Tukey post-hoc testing. D Blood glucose demonstrated main effects of diet ( P < 0.0001) and acute exercise ( P < 0.0001). E Ketones were also regulated by diet ( P < 0.0001) and acute exercise ( P < 0.0001). F Lactate was higher in STZ-KETO compared to other groups (diet main effect P < 0.0001). For ( D – F ): n = 10/group. Data ( D – F ) were analyzed by 2-way ANOVA and Tukey post-hoc testing. For ( A – C ) gray circles represent CON-CHOW, blue circles represent STZ-CHOW, and orange circles represent STZ-KETO. For ( D – F ) black circles represent pre-exercise data and green circles represent post-exercise data with lines connecting repeated measures from the same mouse. Source data are provided as a Source Data file.

Article Snippet: Blood ketones were measured using Precision Xtra Blood Glucose & Ketone Monitoring System (Abbott, 9881465).

Techniques:

Journal: Nature Communications

Article Title: A ketogenic diet enhances aerobic exercise adaptation and promotes muscle mitochondrial remodeling in hyperglycemic male mice

doi: 10.1038/s41467-026-69349-5

Figure Lengend Snippet: Normoglycemic control mice were fed standard chow (CC) or a ketogenic diet (CK) for 16 weeks. Half of the mice underwent voluntary wheel running (exercise-trained) for the last 8-weeks of dietary treatment, while the remainder were housed in static cages and remained sedentary. A Body mass ( P < 0.0001), B fat mass ( P < 0.0001), ( C ) and random glucose ( P < 0.0001) were decreased by exercise-training. For ( A – C ), Sedentary: CON-CHOW n = 7/group, CON-KETO n = 16/group; Exercise-Trained: CON-CHOW n = 8/group, CON-KETO n = 16/group). D Glucose tolerance was impaired by a ketogenic diet, as assessed by a higher area under the curve ( E ) ( P < 0.0001, n = 6/group). F Blood ketones were significantly higher in KETO-fed mice ( P < 0.0001; Sedentary: CON-CHOW n = 7, CON-KETO n = 8; Exercise-trained: n = 8/group) G VO 2 peak was higher in sedentary KETO-fed mice, but no change in aerobic adaptations to training were noted between CHOW- and KETO-fed mice. Main effects of diet ( P = 0.0219) and exercise-training ( P < 0.0001) were observed, and there was a diet-training interaction ( P = 0.0461). H Exercise performance (time to exhaustion) was enhanced by training ( P < 0.0001), but was not impacted by diet. For ( G ) and ( H ), Sedentary: CON-CHOW n = 7; CON-KETO n = 16, Exercise-trained: CON-CHOW n = 8; CON-KETO n = 16). I Muscle protein markers of glucose metabolism, lipid metabolism, and mitochondrial content were assessed in gastrocnemius lysates by Western blotting ( n = 6/group). J After 16-wks of ketogenic diet feeding, mice were randomized to receive 1-wk of carbohydrate restoration (CHOW diet) or a further week of ketogenic diet. K Blood glucose ( P < 0.0001), ( L ) Blood ketones ( P < 0.0001), and [M] time to exhaustion ( P = 0.0213) were impacted by carbohydrate refeeding ( n = 8/group). Data from ( A – I ) and ( K – M ) are presented as mean ± SEM. Data were analyzed by 2-way ANOVA followed by Tukey post-hoc testing. For ( A – I ) grey circles represent CON-CHOW and pink circles represent CON-KETO. For ( K – M ) pink circles represent KETO-KETO, and teal circles represent KETO-CHOW (1-wk carbohydrate restoration). Source data are provided as a Source Data file. Panel [J] c reated in BioRender. Lessard, S. (2026) https://BioRender.com/9sgnbgp .

Article Snippet: Blood ketones were measured using Precision Xtra Blood Glucose & Ketone Monitoring System (Abbott, 9881465).

Techniques: Control, Western Blot

Journal: Nature Communications

Article Title: A ketogenic diet enhances aerobic exercise adaptation and promotes muscle mitochondrial remodeling in hyperglycemic male mice

doi: 10.1038/s41467-026-69349-5

Figure Lengend Snippet: Both treatment groups had reduced muscle and liver glycogen stores, higher muscle mitochondrial density and size, and a larger proportion of oxidative muscle fibers. The ketogenic diet (KETO) also increased rates of fatty acid oxidation at rest and during exercise- independent of exercise-training status. In the absence of exercise, KETO normalized blood glucose levels, increased blood ketones, and increased fat mass compared to chow-fed mice. When combined with exercise training, KETO-fed mice had even larger reductions in blood glucose, while KETO-induced increases in blood ketones were attenuated. In hyperglycemic mice, only those treated with KETO displayed exercise-induced increases in capillary density and VO 2 peak, demonstrating diet-training interactions. Created in BioRender. Lessard, S. (2026) https://BioRender.com/ mr1t7p6.

Article Snippet: Blood ketones were measured using Precision Xtra Blood Glucose & Ketone Monitoring System (Abbott, 9881465).

Techniques: