Take a look at the long protein that stretches through the entire sarcomere that is called the giant protein TITIN. It is a sensor of stretch and contraction and passes through the M-band and the Z-band and affects muscle gene expression powerfully.In this post, I explore the research and theory behind the new form of exercise I have been using now that I am to be 76 this August. It is a combination of standard exercises in some sense, so it is not wholly new and could not be because exercise is simply muscle contraction or stretch.
After looking over the research and using my self-experiment, I have come to a tentative conclusion that targeting TITIN and another sensor in the muscle cell is a useful model of effective exercise. It is a model that can help you and has helped me to design an exercise routine and think about the purpose of exercise.
My basic goals are to
- stave off sarcopenia (wasting of lean muscle),
- limit inflammation (but use it as an acute signal),
- preserve the alpha-motor neurons (they fire the FT fibers) and their signals
- produce acute signals of BDNF (brain derived neuronal growth factor),
- preserve mitochondrial density and function, and
- stimulate (acutely, not chronically) protein synthesis,
- maintain high anabolic and sex hormone production.
That sounds like a big challenge, but it is not so hard to do since I have spent a lifetime doing that in following Evolutionary Fitness, which I developed in the 1980s and summarized in my book, The New Evolution Diet. The challenge now is to do this without loading my joints or over-loading my adaptive capacity. I find it extraordinary that older people are often put on the same old exercise technology used by body builders and recommended by exercise physiologists --- 3 sets of 10 reps with 80% of the one-repetition maximum, three times a week. The experiments that I have read that track response and stress almost always show that the old-timers experience a rise in stress hormones such as cortisol (so do lots of people who overdo it in the gym) and often experience a rise in inflammation. That they still manage to gain strength and muscle mass is a very strong endorsement of weight lifting, but it could be done much more efficiently in my view. The rise in cortisol and inflammation limit and may even prevent the gains that are sought.
The easiest things to temper the pace of aging are to eat as detailed in my previous post.
In developing my new approach to exercise, I was concerned about the slow rate of force development that occurs with aging, which is attributable to the degeneration of the alpha motor neurons in the spine, and with the imbalance between agonist and antagonist muscles that lead to stiffness, poor balance, and the impaired movement shown in the aged. The muscle cells of the aged take on a disorganized state, with a mixing of fiber types, diffuse signaling of the motor neurons as they diminish in size and signaling strength, intrusion of connective tissue, and lessened density of mitochondria. As the motor neurons diminish in number and firing strength, they fire more broadly over the muscle cells and they become less coordinated. FT fibers are lost and the remaining fibers look like a mass of disorganized, undifferentiated fibers.
The inability of aged muscles to absorb force (such as in landing from a jump) imposes a higher load on the joints and connective tissues. This is partly due to the inability of the agonist muscles to lengthen under load and also due to the excess tone or stiffness of the antagonist muscles. A summary of what follows would be this:
- Point number one of my exercise is to increase the ability of the agonist muscle to lengthen under load and diminish the resistance from the antagonist muscle.
- Point number two is to increase the signaling to the FT fibers, which has the side benefit of improving the alpha motor neuron connection, firing, and signal conductance.
- Point number three is to increase the rate at which I can develop force --- rapid force production is the key.
- Point number four, and this is a key, is to improve the integrity of the muscle cell to prevent its fall into a disorganized state. I think the alpha motor neuron activation and measures of muscle cell size and stress such as the giant elastic protein titin and dystrophin are big factors here.
- Point 5, keep the mitochondria in the muscle dense and active, when you lose enough of them the cell goes into a death program.
- Point 6, hang on to the nuclei of your muscle cells. Lose them and you lose muscle cell size.
The muscle cells diminish through a loss of cell number or a loss of cell size. Disorganized cells may actually be larger than organized ones, but they are lost because disorganized cells are removed. The aging must contend with cell atrophy, which is an active process under genetic control. These atrogenes (atrophy producing genes) promote the activity of the ubiquitin-proteasome pathways that actively destroy the muscle cell. Diabetes, cancer cachexia, renal failure, fasting, and denervation (loss of motor neurons) lead to cell death through activation of the atrogene pathways (atrogin-1/MFb1 and MuFR1 have been identified as the primary atrogenes). The atrogenes seem to be the master genes for muscle wasting.
Insulin, acute insulin, not chronic insulin, and IGF-1 induce Akt action. So, rather than making muscle grow, Akt action primarily works by turning down the muscle-wasting atrogenes. It is simple to activate the Akt (and downstream the mTOR) pathway --- exercise induces muscle-produced IGF-1 and eating protein or consuming BCAAs induces an acute release of insulin. Both activate Akt. Carbohydrates release insulin, which up regulates Akt, but the activation is long-lasting and quickly becomes chronic if excess carbohydrate intake leads to insulin resistance. Note, that diabetics suffer muscle wasting at least partly because they become insulin resistant and fail to activate Akt.
Akt-1 is the important pathway for muscle growth and it is activated by exercise. Passive stretch strongly activates Akt signaling and FT fiber development. Akt expression also up regulates mTOR expression and muscle growth. Protein consumption also increases mTOR expression, which seems to be an energy sensor or nutrient sensor.
Interestingly, blocking myostatin, a limiter of muscle size, seems to produce larger but less effective muscles. The FTb fibers, the ones I prize most, form disorganized tubular structures that do not correlate with force production when myostatin is blocked. A myostatin blocker, the holy grail of body builders, leads to bigger, less functional muscles, a price they may be willing to pay.
The inflammatory pathways, through increased levels of TNF-alpha, the cytokine IL-6, and myostatin, are involved in upregulating the atrogenes that cause muscle atrophy. PGC-1alpha is the master regulatory gene for mitochondrial biogenesis, which is crucial for muscle preservation. A loss of mitochondrial density in muscle not only reduces its effective energy and strength, it leads to either the death of the cell or its atrophy. BCAAs improve PGC-1alpha function and expression so that mitochondrial biogenesis is activated. So does intermittent fasting.
Atrophy is the enemy of aging muscle, more so than a lack of anabolic or growth factors. Aging muscle can grow, but only if the balance of atrophy versus anabolism moves to a positive balance acutely. Chronic expression of an anabolic state, paradoxically to a homeostatic point of view, leads to muscle atrophy. But, unfortunately for the homeostatic model, cell size is not a homeostatic variable under genetic control of the muscle cell. Thus, acute changes in atrophy versus anabolism seem to be essential to preserving or growing muscle cell size. Inhibiting cell turnover does not seem to influence protein breakdown, which primarily occurs in the cell to reduce its size.
Conclusion: sarcopenia, at the current state of knowledge, seems to primarily occur through a loss of muscle cell size rather than number. The cells seem to adjust in size through loss of organelles, cytoplasm, and proteins in such a way as to preserve the size of the nuclear domain, the cell domain surrounding the muscle nuclei. Thus, loss of muscle size occurs through loss of nuclei within the cell. And, we know that nuclei are lost when motorneurons fail to signal the nuclei. Disuse, oxidative damage to the neurons or neural plate junction at the muscle, inflammatory damage, or atrogene expression are factors in the loss of nuclei of muscle cells.
So, the bottom line is: preserve muscle, keep your myonuclei, the nuclei of your muscle cells. Two major points follow:
- This is primarily linked to the alpha signaling of motorneurons. Evidence comes from experiments that down regulate the opposing beta signals to the motorneurons, which is shown to result in hypertrophy and a conversion from slow to fast fibers. That says, in short, that increasing alpha signaling produces hypertrophy and slow to fast muscle fiber conversion. We know how to do this and my “system” does it very well (more below)
- The interesting link in muscle signaling is that it depends on mechanical load at the sarcomere, the basic unit of muscle contractive machinery, which is transmitted from there to the nucleus to affect muscle gene expression.
Now, we are really getting somewhere. The giant, elastic protein titin spans half the sarcomere from the Z disk to the M band and interacts with a large number of muscle proteins. Down in the M-band there is a region that alters gene expression that is affected by stretching or contraction of titin. In the absence of stretching or contraction of the titin protein, SRF (serum response factor) a muscle gene expression factor is exported from the muscle cell nucleus. Without SRF, it seems muscle does not grow. Experimental depletion of SRF genes causes severe muscle hypoplasia.
There is another mechanical sensor in muscle that could play a role in muscle size. Dystrophin glycoprotein complex (DGC) anchors the muscle skeleton to the cell membrane. DGC couples the working part of the cell to its membrane and is essential for translating muscle contraction into force. Dystrophin is lost when muscle atrophies and may even be part of the atrophic signaling. Dystrophin measures the disuse of a muscle and may be an active force in disuse atrophy.
So, we have at least two important mechanical sensors measuring stress on the muscle cell or disuse --- titin (contraction or stretch) and dystrophin (disuse). I don't think one can understand why stretching a muscle causes it to become larger unless you recognize that the TITIN long protein is stretched and dystrophin is stressed. Nor can one understand disuse atrophy without recognizing that dytrophin is a sensor of disuse and functions as a trigger for the atrogenes.
This post has gotten to be too long, so the exercise that I developed with these insights will have to wait for the next post. Hint: the stress sensors and how they alter gene expression play a large part of it.
