Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) often requires caloric restriction (CR) to reduce hepatic fat, but CR can compromise muscle mass and function. Resistance training and whey protein are anabolic stimuli, yet their independent and combined effects under substantial CR are unclear. Methods: In a 4-week randomized, double-blind trial, adults with MASLD (n = 45) under ~30% CR were allocated to four groups: resistance training with whey protein supplementation (E-PRO), resistance training with placebo (E-PLA), whey protein supplementation only (PRO), or placebo only (PLA). PRO groups consumed 1.5 g·kg⁻¹·day⁻¹ protein, while PLA groups consumed 0.8 g·kg⁻¹·day⁻¹. Exercise groups performed supervised exercise 5 days/week. Outcomes included body composition and isokinetic muscle function. Results: Across ~30% CR, all groups reduced body weight and fat mass without skeletal muscle mass loss; no between-group differences in body composition changes were observed. For peak torque, E-PRO improved across all regions except trunk, E-PLA improved except non-dominant shoulder flexors and trunk flexors, PRO improved non-dominant knee flexors and shoulder extensors, and PLA showed no change. For total work, E-PRO and E-PLA increased across all regions PRO improved dominant knee extensors/flexors and shoulder extensors; PLA increased only non-dominant knee extensors. E-PRO and E-PLA exceeded PLA for multiple knee/shoulder/trunk outcomes. Conclusions: In individuals with MASLD undergoing severe CR, ≥0.8 g·kg⁻¹·day⁻¹ of protein preserves skeletal muscle mass. However, the anabolic synergy of resistance training and protein for functional adaptation appears to be blunted by the substantial energy deficit.

Objectives: The aim of this study was to explore the combined effects of resistance exercise and whey protein supplementation on plasma irisin levels in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) under a 30% calorie-restricted weight loss diet. Methods: Thirty adult patients with MASLD were randomized into the following three groups for a 4-week intervention: calorie restriction group (CR) (n = 8), CR with resistance exercise group (EX) (n = 11), and CR with resistance exercise and whey protein group (EX + P) (n = 11; 0.7 g/kg per day). All participants received boxed meals providing 70% of their total energy expenditure. The participants in the resistance exercise groups performed full-body resistance exercises 5 days/week (50–75% one-repetition maximum). Plasma irisin level, controlled attenuation parameter (CAP), and body composition were assessed before and after the intervention. Results: Plasma irisin levels significantly increased in the EX (+2.24 ng/mL, p = 0.016) and EX + P (+4.86 ng/mL, p = 0.004) groups but not in the CR group. Muscle mass increased significantly only in the EX + P group. The CAP decreased in all groups. The change in irisin level was negatively correlated with the change in CAP (r = −0.459, p = 0.032). Conclusions: Resistance exercise under calorie-restricted conditions effectively increased plasma irisin levels in patients with MASLD, whereas caloric restriction alone did not. Furthermore, a stronger increasing trend in the plasma irisin levels was observed with whey protein supplementation. An increase in irisin levels was significantly associated with hepatic fat reduction, suggesting that irisin may serve as a biomarker reflecting improvements in hepatic steatosis following lifestyle intervention.