Myostatin Inhibition in Combination with Strength Training and Amino Acid Supplementation
Myostatin inhibition, strength training, and forms of amino acid supplementation, such as leucine supplementation, all have data to show that they can improve muscle mass. They have all been used in human trials as possible treatments for sarcopenia, the age-related loss of muscle mass and strength that ultimately leads to frailty. That strength training works, and works fairly well, to both improve muscle mass and reduce age-related mortality suggests that a sizable fraction of the problem is the pervasive lack of activity and exercise in older populations. Myostatin inhibition could in principle produce larger effects, based on the outcome of loss of function mutations, in which the affected individuals are very heavily muscled. In human trials of anti-myostatin antibodies, the gains have been much smaller.
It has been frequently reported that myostatin inhibition increases muscle mass, but decreases muscle quality (i.e., strength/muscle mass). Resistance exercise training (RT) and essential amino acids (EAAs) are potent anabolic stimuli that synergistically increase muscle mass through changes in muscle protein turnover. In addition, EAAs are known to stimulate mitochondrial biogenesis.
We have investigated if RT amplifies the anabolic potential of myostatin inhibition while EAAs enhance muscle quality through stimulations of mitochondrial biogenesis and/or muscle protein turnover. Mice were assigned into ACV (myostatin inhibitor), ACV+EAA, ACV+RT, ACV+EAA+RT, or control over 4 weeks. RT, but not EAA, increased muscle mass above ACV. Despite differences in muscle mass gain, myofibrillar protein synthesis was stimulated similarly in all versus control, suggesting a role for changes in protein breakdown in muscle mass gains.
There were increases in MyoD expression but decreases in Atrogin-1/MAFbx expression in ACV+EAA, ACV+RT, and ACV+EAA+RT versus control. EAA increased muscle quality (e.g., grip strength and maximal carrying load) without corresponding changes in markers of mitochondrial biogenesis and neuromuscular junction stability.
In conclusion, we showed that addition of resistance exercise training, but not dietary EAAs, to the myostatin inhibition further increased muscle mass through the attenuation of muscle protein breakdown with proportionate improvements in muscle strength. Interestingly, addition of dietary EAAs to the myostatin inhibition with or without resistance exercise training improved muscle quality. Thus, dissection of the underlying mechanisms behind the combined positive effect of dietary EAAs and resistance exercise training on muscle mass and quality can shed light on the discovery of effective therapeutics against muscle wasting such as sarcopenia.