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.
but... but... Leucine activates mTor.... mTor bad... makes you die sooner.
and... and... myostation regulates energy homeostasis in the heart and prevents heart failure... inhibition no good... makes you die sooner.
Also of interest:
Antimyostatin Treatment in Health and Disease: The Story of Great Expectations and Limited Success
"mTor bad... makes you die sooner.
and... and... myostation regulates energy homeostasis in the heart and prevents heart failure... inhibition no good... makes you die sooner."
Perhaps more muscle mass is a trade off, whereby one can have less frailty in later years in exchange for a couple years less of life. If there is such a trade off and choice, I would take greater health span (i.e., less frailty) over longer life span.
Yeah, well, what i said was a bit tongue in cheek.
In an aging context where the mTor complexes are OVER-activated it is beneficial to inhibit the OVER-activation that disrupts tissue/cell homeostasis.
But it is equally beneficial not to inhibit mTor too much, too long or even completley because it regulates protein synthesis and cell growth, is crucial for the maintenance of cells through its association with ribosomes, and is involved in cellular metabolic regulation.
In a cancer context mTor inhibition (as completely as possible) impedes both cell proliferation and migration along with aberrant metabolic pathways.
The mTor complexes are sensitive to distinct stimuli, as mTORC1 is sensitive to nutrients (esp. Leucin) while mTORC2 is regulated via PI3K and growth factor signaling.
There is an upstream reason for mTor's over-activation in aged cells/tissue. Just indiscrimately hammering mTor with rapamycin and analogues seems to be a very crude method to deal with the over-activation, which won't be without serious side-effects., esp. long term.
Now, why would one need to use Leucin to activate the nutrient sensing mTorc1 in aged muscle when mTor is already over-activated?