Declines in muscle protein synthesis account for short-term muscle disuse atrophy in humans in the absence of increased muscle protein breakdown

Abstract

Background: We determined the short-term (i.e. 4 days) impacts of disuse atrophy in relation to muscle protein turnover [acute fasted-fed muscle protein synthesis (MPS)/muscle protein breakdown (MPB) and integrated MPS/estimated MPB].

Methods: Healthy men (N = 9, 22 ± 2 years, body mass index 24 ± 3 kg m^-2 ) underwent 4 day unilateral leg immobilization. Vastus lateralis (VL) muscle thickness (MT) and extensor strength and thigh lean mass (TLM) were measured. Bilateral VL muscle biopsies were collected on Day 4 at t = -120, 0, 90, and 180 min to determine integrated MPS, estimated MPB, acute fasted-fed MPS (l-[ring-¹³ C₆ ]-phe), and acute fasted tracer decay rate representative of MPB (l-[¹⁵ N]-phe and l-[² H₈ ]-phe). Protein turnover cell signalling was measured by immunoblotting.

Results: Immobilization decreased TLM [pre: 7477 ± 1196 g, post: 7352 ± 1209 g (P < 0.01)], MT [pre: 2.67 ± 0.50 cm, post: 2.55 ± 0.51 cm (P < 0.05)], and strength [pre: 260 ± 43 N m, post: 229 ± 37 N m (P < 0.05)] with no change in control legs. Integrated MPS decreased in immob vs. control legs [control: 1.55 ± 0.21% day^-1 , immob: 1.29 ± 0.17% day^-1 (P < 0.01)], while tracer decay rate (i.e. MPB) (control: 0.02 ± 0.006, immob: 0.015 ± 0.015) and fractional breakdown rate (FBR) remained unchanged [control: 1.44 ± 0.51% day^-1 , immob: 1.73 ± 0.35% day^-1 (P = 0.21)]. Changes in MT correlated with those in MPS but not FBR. MPS increased in the control leg following feeding [fasted: 0.043 ± 0.012% h^-1 , fed: 0.065 ± 0.017% h^-1 (P < 0.05)] but not in immob [fasted: 0.034 ± 0.014% h^-1 , fed: 0.049 ± 0.023% h^-1 (P = 0.09)]. There were no changes in markers of MPB with immob (P > 0.05).

Conclusions: Human skeletal muscle disuse atrophy is driven by declines in MPS, not increases in MPB. Pro-anabolic therapies to mitigate disuse atrophy would likely be more effective than therapies aimed at attenuating protein degradation.

Keywords: Atrophy; Immobilization; Muscle; Protein breakdown; Protein synthesis.

Figure 1

Schematic representation of study design.

Figure 2

Schematic representation of infusion trial.

Figure 3

Thigh lean mass (A), vastus lateralis (VL) muscle thickness (B), and maximal voluntary isometric contraction torque (C) of the control and immobilized (immob) leg pre and post 4 days of single leg immobilization in health young men. **P < 0.01, *P < 0.05.

Figure 4

Over the 4 day study period in control and immobilized legs (A) muscle protein synthesis in % day⁻¹, (B) fractional growth rate in % day⁻¹, (C) fractional breakdown rate in % day⁻¹, and (D) correlation between the change in MPS and change in VL MT. **P < 0.01, *P < 0.05.

Figure 5

(A) Acute fasted and fed MPS rates in % h⁻¹ in control and immobilized legs. (B) The absolute change in integrated or acute muscle protein synthesis in % day⁻¹ (assuming two‐thirds of the day is spent fasted and one‐third fed). (C) Acute fasted tracer decay rate (k h⁻¹ value). *P < 0.05.

Figure 6

Correlation between change in fasted to fed muscle protein synthesis vs. (A) change in fasted to fed p‐rpS6 and (B) change in in fasted to fed p‐4E‐BP1.

Figure 7

Representative immunoblots for muscle signalling pathway activity.