Abstract
Cell migration is central to skeletal muscle repair following damage. Leucine and β-Hydroxy β-methylbutyric acid (HMB) are supplements consumed for recovery from muscle damaging exercise in humans, however, their impact on muscle cell migration with age is not yet understood. We hypothesised that replicatively aged (“aged”; P46–P48) myoblasts would be less efficient at basal and supplemented repair versus parental controls (“control”; P12–P16). Aged and control myoblasts were scratch-damaged and migration velocity, directionality and distance assessed over 48 h in the absence and presence of leucine (10 mM) or HMB (10 mM) ± PI3K/Akt (LY294002 10 μM), ERK (PD98059 5 μM) or mTOR (rapamycin 0.5 μM) inhibition. Opposing our hypothesis, aged cells displayed increased velocities, directionality and distance migrated (P < 0.001) versus control. Leucine and HMB significantly increased (P < 0.001) the same parameters in control cells. The supplements were with smaller, albeit significant impact on aged cell velocity (P < 0.001) and in the presence of HMB only, distance (P = 0.041). Inhibitor studies revealed that, PI3K and ERK activation were essential for velocity, directionality and migration distance of aged cells in basal conditions, whereas mTOR was important for directionality only. While PI3K activation was critical for all parameters in control cells (P < 0.001), inhibition of ERK or mTOR improved, rather than reduced, control cell migration distance. Enhanced basal velocity, directionality and distance in aged cells required ERK and PI3K activation. By contrast, in control cells, basal migration was underpinned by PI3K activation, and facilitated by leucine or HMB supplementation, to migration levels seen in aged cells. These data suggest that replicatively aged myoblasts are not anabolically resistant per se, but are capable of efficient repair, underpinned by altered signaling pathways, compared with unaged control myoblasts.
Highlights
During the human lifespan, a gradual loss of skeletal muscle mass and strength occurs, referred to as sarcopenia
We hypothesised that: (1) replicatively aged (P46–P48; ‘‘aged’’) myoblasts would be less efficient at damage repair versus control (P12–P16; ‘‘control’’); (2) leucine and Hydroxy bmethylbutyric acid (HMB) would increase the migration potential in control but not aged cells and; (3) that the PI3K and ERK but not mTOR pathways would be required for effective basal migration in both models
With the supplementation of leucine and HMB, the capacity of the control cells to migrate is increased to that of the aged cells. This implies that 1, the control cells are more responsive to the supplements or 2, that maximal migration capacity has been attained in aged cells under basal conditions and supplements cannot improve their migration capability
Summary
A gradual loss of skeletal muscle mass and strength occurs, referred to as sarcopenia. While muscle mass and strength in young individuals can be preserved through nutritional supplementation, it is reported that muscle in older adults displays a level of anabolic resistance (Breen and Phillips 2011). An essential amino acid, is reportedly a potent anabolic agent (Koopman et al 2006) and is consumed following damaging exercise, with the aim to improve muscle regeneration (Farup et al 2014). In young recreationally active males, whey protein, which contains high doses of leucine (8 g per 100 g), increased muscle satellite cell number at 48 h post eccentric damage, compared with control (Farup et al 2014)
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