The pivotal role of pro-anabolic modulators on muscle mass and function: a systematic review

Sarcopenia is a progressive skeletal muscle disorder characterized by the loss of muscle mass and strength. The concept of pro-anabolic modulators (including vitamin D, leucine, omega-3 fatty acids, and probiotics) as nutritional agents to counteract sarcopenia has been introduced as a promising strategy to restore anabolic balance in aging muscle. This systematic review aimed to synthesize recent evidence on the effectiveness of these compounds on muscle mass and physical performance. A total of 53 randomized controlled trials were included: 30 evaluated vitamin D, 8 leucine, 9 omega-3, and 6 probiotics. Across studies, although results for vitamin D were heterogeneous, daily supplementation suggested a more consistent potential for beneficial effects compared to bolus regimens, particularly when co-administered with other agents or physical exercise. Leucine demonstrated greater efficacy when combined with resistance training or other pro-anabolic agents. Most studies on omega-3 fatty acids reported improvements in muscle strength and functional outcomes, especially in long-duration interventions. Probiotics also showed promising results, with almost all studies reporting positive effects on muscle mass and strength, despite variability in strains and protocols. Given the low to very low certainty of evidence for most outcomes (except for physical performance, which reached moderate certainty), these results should be interpreted with caution, despite a general trend toward favorable outcomes. These findings suggest that combining pro-anabolic modulators (or pairing them with exercise or additional nutrients) may enhance their efficacy on muscle-related outcomes. Further research is warranted to define optimal protocols and to clarify the mechanisms underlying their potential synergistic effects.