Purpose Due to the mechanistic role of myostatin and follistatin in modulating muscle mass, shifts in the follistatin to myostatin ratio (F:M) may help explain changes in muscular size in response to resistance training (RT). The present study examined whether differential responses in follistatin and myostatin occur based on the amount of active musculature in a RT program in middle-aged men. Methods Forty middle-aged men (age = 46.5 ± 3.1 years) were randomly assigned to 1 of 4 groups, upper-body RT (UB; n = 10), lower-body RT (LB; n = 10), combined RT (UB + LB; n = 10) or control (C; n = 10). The training protocol consisted of three exercise sessions per week for 8 weeks. Blood samples were obtained at baseline and 48 h after the final session of the training program. Results Muscle mass significantly increased (p < 0.05) following UB = 0.76 ± 0.46 kg, LB = 0.90 ± 0.29 kg, UB + LB = 1.38 ± 0.70 kg, compared to no changes after control. Serum follistatin increased in the LB = 0.24 ± 0.06 ng mL−1, UB = 0.27 ± 0.17 ng mL−1, UB + LB = 0.50 ± 0.18 ng mL−1, while serum myostatin decreased in the LB = − 0.11 ± 0.08 ng mL−1 and UB + LB = − 0.34 ± 0.23 ng mL−1, but not UB = 0.07 ± 0.16 ng mL−1. Further, change in concentration following training was larger between UB + LB and either LB or UB alone for both follistatin and myostatin. Conclusions Both UB and LB increase muscle mass and alter the F: M ratio; however, the change in these endocrine markers is approximately twice as large if UB and LB is combined. The endocrine response to RT of myostatin and follistatin may depend on the volume of muscle mass activated during training.

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