Gain muscle mass without doing sport, just by swallowing a pill… Is this fiction? Researchers have managed to cause muscle hypertrophy without the slightest effort, at least in mice. Their work, although it is far from being directly transposable to humans, sheds light on the role of an essential player involved in regulating muscle mass: the FoxO transcription factor.
Mice That Gain Muscle Mass Without Doing Physical Activity
The research team aimed to understand better what happens in cases of cachexia. This situation, characterized by involuntary weight loss and muscle atrophy, manifests itself in cases of extreme malnutrition or during serious illnesses such as cancer. Developing this condition for a patient is not an encouraging sign, which limits the chances of recovery.
FoxO Is A Marker Of Muscle Wasting
The researchers were interested in a compound, FoxO (from the English forkhead box O ), the quantity of which increases in the muscle in the event of muscle wasting. They developed a technique to neutralize it and tested its effects in mice. Two groups of animals were affected by a disease conducive to the occurrence of cachexia (cancer for some, a generalized blood infection for others). In contrast, the third group was made up of healthy animals.
In the first two groups, the administration of the FoxO inhibitor succeeded in stopping the occurrence of muscle atrophy. In healthy mice, it had an unexpected effect: it caused muscle hypertrophy without the animals being subjected to physical training. This result encourages us to take a closer look at the role and mode of action of FoxO.
What Is A Transcription Factor?
FoxO is a member of the family of transcription factors, which are responsible for driving gene expression. Our genetic heritage carries many genes, which are not all active at the same time in each of the cells of our body. Some express themselves and allow the production of proteins with various roles, while others remain silent. This action or inaction depends on the presence of particular compounds and transcription factors. They attach to a given gene and, like a switch, turn it on or off.
FoxO Controls Muscle Breakdown During Extreme Situations
The FoxO family comprises four mammal members: FoxO1, FoxO3a, and FoxO4, which are present throughout the organism, and FoxO 6, which is explicitly found in neurons.These transcription factors are involved in cell differentiation and proliferation. They would influence the longevity of organisms and could play a tumor-suppressing role. They also provide an essential function within the muscles.
FoxO Is Involved In Muscle Atrophy
The amount of FoxO increases in muscle tissues under different circumstances: malnutrition, generalized inflammation, cancer, infectious diseases, burns, heart failure, etc. This increase in FoxO levels causes a catabolic state: muscle proteins are broken down, which releases the amino acids that constitute them.
The body can then reuse these to produce glucose in the liver through the gluconeogenesis mechanism to provide energy to vital organs or to manufacture new proteins. Muscles represent the largest protein reserve in our body, which will be mobilized when facing a dangerous situation. FoxO is, therefore, one of the survival mechanisms called upon in the event of an extreme situation. But there is, of course, a high price to pay: the destruction of muscle tissue, which can quickly become damaging.
FoxO Activates Genes That Break Down Muscle Proteins
FoxO stimulates the expression of genes involved in the breakdown of muscle proteins, such as those allowing the production:
- atrogin-1 and MuRF-1, enzymes that attach to the myofibrils making up the muscles to break them down
- Cathepsin L, another enzyme responsible for fragmenting proteins, is located in the cell compartment, allowing the recycling of the body’s components, the lysosome.
FoxO will also block the expression of other genes, such as that of PGC‐1β for example, which allows the production of a compound, increasing energy expenditure within cells. By acting in this way, FoxO saves energy in critical periods.
FoxO Maintains Muscle Mass Balance
If FoxO is active in these circumstances, it also plays a role within the muscles in everyday situations, maintaining muscular balance. It activates the expression of myostatin, a protein that blocks muscle growth. In particular, it supports muscle stem cells (satellite cells) in a dormant state and limits protein synthesis. When FoxO is neutralized, the brake is released, which leads to the muscle hypertrophy observed in mice.
During Resistance Training, The Amount Of FoxO Decreases
To gain muscle mass, FoxO must, therefore, be muzzled. Researchers were interested in the evolution of its level in the muscle by performing biopsies in athletes, first during an 8-week resistance training phase, then during a phase of inactivity. During the first period, which led to muscle hypertrophy of around 10%, the level of FoxO1 decreased within the muscles. During the second phase, which caused a loss of 5% of muscle mass, the level of FoxO1 increased. The evolution of the FoxO level in the muscle was inverse to that of the Akt protein kinase level in active form. This is part of the Akt/mTOR signaling pathway, which allows the synthesis of proteins essential for muscle development.
The Enzyme Akt Silences FoxO
When the protein kinase Akt is activated during sports practice or when the body has sufficient resources (signaled by the increase in the level of insulin and growth factors IGF1), it will transfer a group of chemical phosphate to the transcription factor FoxO. This reaction occurs within the cell, in the liquid medium (the cytoplasm) filling it. In this form, FoxO becomes captive to the cytoplasm and cannot reach the cell’s nucleus, where its target genes are located. It can, therefore, no longer oppose muscular development. Until we have a FoxO inhibitor, the only solution to silence it remains to train and not starve yourself. Taking vitamin D could also help. Indeed, researchers have recently shown that it prevents muscle atrophy by tempering the activity of FoxO1.
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