# Ketogenic Diet Plus Resistance Training Applied to Physio-Pathological Conditions: A Brief Review
## 3 Insulin-Dependent and -Independent Responses to Resistance Training  
The musculoskeletal system represents a unique structure in which bones, muscles, ligaments, soft tissues, and tendons are intricately interconnected [52] and coordinated by neuromuscular junctions [53]. As a type of strength training, resistance exercise is characterized by the physical effort exerted when skeletal muscles work against a given weight or external force. Numerous positive health and physical performance adaptations have been reported when the stressful stimulus of resistance exercise is administered with appropriate time intervals and optimal recovery time in different phenotypes [54; 55; 56; 57; 58; 59]. This remarkable plasticity is responsible for adaptations in physiological and pathophysiological conditions [60; 61; 62; 63]. This ability of muscles to adapt to external stimuli relies on different signaling pathways and secondary messengers, which are responsible for maintaining muscle status. The concept of muscle status is encouraged, given that it encompasses not only quantity (skeletal muscle mass) but also gives relevance to intramuscular structural features (muscle quality), endocrine activity (insulin), and movement functionality. In particular, the mechanistic Target of Rapamycin complex 1 (mTORC1) pathway [52], strongly activated by insulin, and the mitogen-activated protein kinase (MAPK) pathway [64] seem to play an essential role in resistance exercise-induced adaptations of musculoskeletal tissue.  
Besides the insulin-mediated response, other biochemical signalers also contribute to muscular plasticity, including the mechano growth factor (MGF), testosterone, and the Protein Kinase B (PKB or AKT), which inhibits the Forkhead Box 1/3 FoxO1/3 pathway, providing an anticabolic stimulus [65]. Additionally, nitric oxide (NO) and amino acids, particularly glutamine and leucine, are involved in these processes. Although leucine directly activates mTORC1 [66; 67], muscle protein synthesis strongly relies on essential amino acids, so focusing on the amino acid profile rather than leucine content alone would be a recommended approach [68]. Interestingly, a recent study in a murine model showed that (D)-3-hydroxybutyrate, the main component of ketone bodies, has positive effects on muscle atrophy and beneficial metabolic reprogramming effects in healthy muscle [69]. Other non-dependent insulin biochemical mechanisms contributing to exercise-induced adaptations include the NF\(\kappa\)B, which is downregulated by inflammation and reactive oxygen species (ROS), and the peroxisome proliferatorator-activated receptor gamma coactivator 1-alpha (PGC-1\(\alpha\)), whose activation is particularly beneficial for mitochondrial  
\begin{table}
\begin{tabular}{l l l l l} \hline \hline
**Markers** & **KD** & **ICKD** & **VLCKD** & **VLCKD + Exercise** \\ \hline HbA1c & Decrease & NR & Decrease & NR \\ \hline TG & Decrease & No changes & Decrease & Decrease \\ \hline HDL & Increase & No changes & No changes & Increase \\ \hline LDL & Decrease & Increase & No changes & Decrease \\ \hline Total cholesterol & NR & Increase & NR & Decrease \\ \hline Fasting glucose & Decrease & Decrease & Decrease & Decrease \\ \hline Insulin & NR & Decrease & NR & Decrease \\ \hline \hline \end{tabular}  
* NR: Not Reported.  
\end{table}
Table 2: The impact of physiological ketosis on metabolic profile.  
health, but more responsive to endurance training [60] (Figure 2). These findings suggest that, even in the absence of continuous peaks of insulin stimulation, increased strength and/or hypertrophy can be achieved due to the intricate mechanisms and alternative pathways that characterizes the human physiology's flexibility.