Until now, the role/impact of skeletal muscle, which is the largest tissue of the human body and possesses an important role in glucose-lipids metabolism and clearance, on glycemic-lipidemic blood profiles, cardiometabolic risk factors and diseases remains largely unknown. Muscle tissue but mostly its components, eg. muscle fibers, lately have been suggested as significant regulators of humans’ metabolism, health and body composition, in a muscle fiber type and size-dependent manner, with participants possessing higher number and sizes of Type I (slow oxidative), IIa (fast oxidative-glycolytic) and low Type IIx muscle fibers (very fast glycolytic) to also characterized by healthier body composition, glycemic-lipidemic blood profiles and lower cardiometabolic risk factors, even if they follow poor lifestyle choices (like inactivity, unhealthy nutrition etc). Complex muscle-organs crosstalk mechanisms have been presented until now, including the fiber type-specific metabolic procedures, expression of myokines-exerkines- myobolites etc, that underlying the regulatory effect of muscle tissue and muscle fibers on humans’ metabolism, health, body composition and cardiometabolic risk factors. However, nutrition, systematic training, and their combinations could change muscle’s metabolic functions, by regulating muscle fiber composition and metabolism, and thus the muscle-organs crosstalk mechanisms, either positively or negatively. All the above will be highlighted during this speech, practical applications will be presented while emphasis will be given to what we do not know until now.