Background:The training of elite skiers follows a systematic seasonal periodization with a preparation period, when anaerobic muscle strength, aerobic capacity, and cardio-metabolic recovery are specifically conditioned to provide extra capacity for developing ski-specific physical fitness in the subsequent competition period. We hypothesized that periodization-induced alterations in muscle and metabolic performance demonstrate important variability, which in part is explained by gene-associated factors in association with sex and age.Methods:A total of 34 elite skiers (20.4 ± 3.1 years, 19 women, 15 men) underwent exhaustive cardiopulmonary exercise and isokinetic strength testing before and after the preparation and subsequent competition periods of the World Cup skiing seasons 2015–2018. Biometric data were recorded, and frequent polymorphisms in five fitness genes, ACE-I/D (rs1799752), TNC (rs2104772), ACTN3 (rs1815739), and PTK2 (rs7460, rs7843014), were determined with specific PCR reactions on collected DNA. Relative percentage changes of cardio-pulmonary and skeletal muscle metabolism and performance over the two seasonal periods were calculated for 160 data points and subjected to analysis of variance (ANOVA) to identify hypothesized and novel associations between performance alterations and the five respective genotypes and determine the influence of age × sex. A threshold of 0.1 for the effect size (h2) was deemed appropriate to identify relevant associations and motivate a post hoc test to localize effects.Results:The preparation and competition periods produced antidromic functional changes, the extent of which varied with increasing importance for anaerobic strength, aerobic performance, cardio-metabolic efficiency, and cardio-metabolic/muscle recovery. Only peak RER (−14%), but not anaerobic strength and peak aerobic performance, and parameters characterizing cardio-metabolic efficiency, differed between the first and last studied skiing seasons because improvements over the preparation period were mostly lost over the competition period. A number of functional parameters demonstrated associations of variability in periodic changes with a given genotype, and this was considerably influenced by athlete “age”, but not “sex”. This concerned age-dependent associations between periodic changes in muscle-related parameters, such as anaerobic strength for low and high angular velocities of extension and flexion and blood lactate concentration, with rs1799752 and rs2104772, whose gene products relate to sarcopenia. By contrast, the variance in period-dependent changes in body mass and peak VO2 with rs1799752 and rs2104772, respectively, was independent of age. Likely, the variance in periodic changes in the reliance of aerobic performance on lactate, oxygen uptake, and heart rate was associated with rs1815739 independent of age. These associations manifested at the post hoc level in genotype-associated differences in critical performance parameters. ACTN3 T-allele carriers demonstrated, compared to non-carriers, largely different periodic changes in the muscle-associated parameters of aerobic metabolism during exhaustive exercise, including blood lactate and respiration exchange ratio. The homozygous T-allele carriers of rs2104772 demonstrated the largest changes in extension strength at low angular velocity during the preparation period.Conclusions:Physiological characteristics of performance in skiing athletes undergo training period-dependent seasonal alterations the extent of which is largest for muscle metabolism-related parameters. Genotype associations for the variability in changes of aerobic metabolism-associated power output during exhaustive exercise and anaerobic peak power over the preparation and competition period motivate personalized training regimes. This may help to predict and maximize the benefit of physical conditioning of elite skiers based on chronological characteristics and the polymorphisms of the ACTN3, ACE, and TNC genes investigated here.