Table 1.

Effects of KD on skeletal muscles.

Animal	KD: Protein:Fat:Carbohydrate Ratio (% Total Energy)	Muscle	Exposure/Pathology	Outcome	Ref.
Male C57BL/6 J mice	KD: 19:61:20	Extensor digitorum longus, soleus, gastrocnemius, and quadriceps femoris	Physically active mice had access to a running wheel	KD-fed mice were more insulin-resistant. KD led to upregulation of PDK4 and ERRα mRNA and protein levels. Effects of KD with running were even greater. PGC-1α mRNA or protein levels did not significantly depend on KD. The amount or function of mitochondria did not depend on KD either.	[59]
Seven-week- old male Sprague–Dawley rats	LKD: (12:87:1); MKD: (16:66:18)	Epitrochlearis and triceps	Swimming exercise (8-week intervention)	Endurance training significantly increased OXCT content in epitrochlearis muscle tissue and additionally increased OXCT protein content. LCT but not MCT diet substantially increased muscle PDK4 protein level. Thus, MCT diet may additively enhance endurance training-induced increases in ketolytic capacity in skeletal muscle without exerting inhibitory effects on carbohydrate metabolism.	[64]
Six-week-old female Jcl:ICR mice	KD: 4.8:94.8:0.1	Gastrocnemius, tibialis anterior, and soleus	-	Circulating levels of FFA increased up to 700% in KD-fed mice. KD increased plasma corticosterone levels 2.9-fold and decreased plasma IGF-1 levels by 60% in comparison. Feeding mice with KD led to upregulation of muscle atrophy-related genes Mafbx, Murf1, Foxo3, Lc3b, and Klf15 in skeletal muscles. Expression of anabolic genes such as Igf1 and Col1a2 is reduced in KD group. mRNA expression of oxidative stress-responsive genes such as Sod1 was significantly increased after KD. Thus, KD can lead to muscle atrophy in which hypercorticosteronemia, hypoinsulinemia, reduced insulin-like growth factor 1 (IGF-1), and oxidative stress are involved.	[54]
C57BL/6 mice	KD: 10:89:1	Quadriceps (QUAD), gastrocnemius (GTN), plantaris (PLN), soleus (SOL), tibialis anterior (TA), and extensor digitorum longus (EDL)	Age-related sarcopenia	No differences in body weight were observed with age or diet. The influence on muscle weight was different between different muscles: GTN significantly decreased in weight from 16 to 26 months after KD and in control. After 26 months, GTN was significantly bigger in KD mice; PLN and SOL had a significantly lower muscle mass after 26 months compared to 16, and there was a trend for higher PLN and SOL muscle weights in 26-month-old mice on KD compared with 26-month-old control. This result in KD mice was associated with a shift in fiber type from IIb to IIa fibers and alterations in a range of molecular parameters, including increased markers of neuromuscular junction remodeling, mitochondrial biogenesis, oxidative metabolism, antioxidant capacity, as well as decreased endoplasmic reticulum stress, protein synthesis, and proteasome activity.	[65]
C57BL/6J male mice	KD: 16.1:83.9:0	Quadriceps, gastrocnemius	Exercise training (ExTr): Mice ran on a treadmill for 3 weeks, 5 days/week, 1 h/day	ExTr increased intramuscular glycogen, whereas KD increased intramuscular triglycerides. Neither KD nor ExTr alone altered mitochondrial content; however, in combination, the KD–ExTr group showed an increase in PGC-1α and markers of mitochondrial fission/fusion. There are no changes in pyruvate oxidative capacity by both exposure. KD and ExTr interventions both enhanced mitochondrial and peroxisomal lipid oxidation and adaptations were additive or synergistic.	[55]
C57BL/6 mice	KD: 9.9:74.4:3	Quadriceps	PGC-1α mKO	KD increased oxygen consumption by muscle in PGC-1α-dependent manner, concomitant with a blunted transcriptional induction of genes involved in fatty acid oxidation and impairment in exercise performance.	[71]
Sedentary Wistar rats	KD: 10:90:0	Extensor digitorum longus	-	Physiological parameters such as twitch or tetanic forces or muscle fatigue did not differ between KD and the control group. Citrate synthase activity and protein levels of Sema3A, citrate synthase, succinate dehydrogenase, cytochrome c oxidase subunit 4, and 3-hydroxyacyl-CoA dehydrogenase were significantly higher in KD group. The 4-week ketogenic diet improves skeletal muscle aerobic capacity.	[70]
Male Fisher 344 rats	KD: 22.4: 77.1:0.5	White and red quadriceps		KD induces weight loss and enhances mitochondrial respiration without increased mitochondrial content in skeletal muscle. Muscle after KD similarly produced less H2O2 despite an increase in mitochondrial respiration and no apparent change in mitochondrial quantity.	[56]
Male Fisher 344 rats	KD: 23:67:10	Gastrocnemius		KD-fed rats have significantly greater mitochondrial ROS production in the gastrocnemius, while mitochondrial glutathione levels were lower. The GTN pyruvate-malate mitochondrial respiratory control was significantly impaired in long-term KD-fed rats, and GTN mitochondrial quantity was lowest in these animals. Rotarod performance was greatest in KD-fed rats.	[68]
C57BL6 mice	KD: 8.6:75.1:3.2	Tibialis anterior	BaCl2 injury	Muscle stem cells (MuSCs) isolated from 3-week KD-fed mice demonstrate a deep quiescent (DQ) state. This state is characterized functionally and transcriptionally as being less committed to a myogenic program but also enhanced resistance to nutrient, cytotoxic, and proliferative stress. Impairment of regeneration of muscle tibialis anterior was shown, when mice had been fasted for 2.5 days and subsequently refed for 1, 2, 3, or 7 days prior to BaCl2 injury.	[72]
C57Bl/6J mice	KD: diets containing 5% sodium butyrate (butyrate) for 8–10 months	Gastrocnemius–plantaris with soleus	Age-related muscle atrophy	KD abolished age-dependent muscle mass loss, and the mice treated with butyrate from 16 months old were protected against muscle atrophy in hindlimb muscles. Diet containing butyrate increased muscle fiber cross-sectional area, prevented intramuscular fat accumulation in the old mice, and improved glucose metabolism in 26-month-old mice as determined by a glucose-tolerance test. The effect of butyrate was not associated with reduced ubiquitin-mediated proteasomal degradation. Butyrate reduced markers of oxidative stress and apoptosis and improved antioxidant enzyme activity. It is supposed that these effects were associated with HDACs inhibition by butyrate.	[73]
C57BL/6J mice	KD: 20:69:10; 20:78:1	Gastrocnemius	Small animal treadmill set to 15 m/min, 0% slope, for 60 min for 5 days	No change of body and muscle mass was observed in two groups of animals after KD with 1% and 10% of protein content compared to control. Only in the KD group with 1% of protein content did the plasma ketone concentration significantly increase with gene expression related to glucose utilization significantly declining in the muscle. In both groups, an increased gene expression related to lipid utilization was observed. Thus, KD with 10% of proteins leads to an increase of lipid oxidation without ketosis and suppression of muscle glucose utilization. However, in both groups, KD treatment did not affect endurance capacity.	[58]
Male Sprague–Dawley rats	KD: 20.2:69.5:10.3	Gastrocnemius	Cage with a resistance-loaded voluntary running wheel	In the presence of a complex II (succinate) substrate, the respiratory control ratio of isolated gastrocnemius mitochondria was higher in animals fed the KD. Complex I (pyruvate + malate) and IV enzyme activity was higher in EXE (exercised using resistance-loaded running wheels) animals regardless of diet. SOD2 protein levels and GLUT4 and PGC1α mRNA expression were higher in EXE animals regardless of diet.	[67]
Male C57BL/6JN mice	KD: 10:89:1	Gastrocnemius		Both subsarcolemmal and intermyofibrillar fractional area was significantly higher in KD mice, consistent with an increase in mitochondrial content in both regions. There was no difference in the average size of mitochondria between diet groups.	[69]