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Pyrroloquinoline Quinone and mTORs

As a general statement, mTORs are cellular regulatory proteins essential for the activation of proteins specific or important to growth and cellular replication.  Almost any factor important to protein synthesis affects mTOR activation to some degree by interacting with the TSC1/TSC2 protein complex.  Relevant to the question, the underlying mechanisms for many tumors and cancers involve dysregulation of mTOR cell signaling pathways (usually an abnormal up-regulation of mTOR components).  Thus, as an approach to controlling the growth of cancerous cell lines, the use of mTOR inhibitors has been proposed.  The question or concern related to PQQ evolves from such observations, specifically the report by Kumar et al. in Anticancer Agents Med Chem. 2015;15:1297-304 (https://www.ncbi.nlm.nih.gov/pubmed/25832358).  These researchers observed that PQQ exposure lessens the growth of human leukemia HL-60 Cells through Inhibition of mTOR.  Thus the question – Could something similar happen in muscle?

The cells in question versus muscle cells:

HL-60 (Human promyelocytic leukemia) cells are derived from a type of blood cells, known as neutrophils.  HL-60 cells proliferate continuously in suspension cell cultures.  Accordingly, they are used in cell proliferation studies or studies in which cells with the characteristics of phagocytic cells, such as neutrophils, are the focus of an investigation.  Phagocytic cells are cells that are recruited to the sites of infection, cell injury, and inflammation.  An interesting observation is that when activated, some of their mitochondrial content gets extruded (cf. http://www.tandfonline.com/doi/full/10.1080/15548627.2015.1063765) in to plasma/blood.   In this regard,  plasma levels of mitochondrial DNA (from phagocytic and the targeted damaged cells) can be used as a marker for the extent of inflammation in human and animal subjects. Phagocytic cells can even generate hydrogen peroxide and superoxide radicals to aid in the chemical modification of inflammatory by-products and cellular debris.

Muscle cells, of course, are different.  In vivo, they do not replicate or “turn-over” rapidly, in contrast to phagocytic cell lines.  Their mitochondria stay intake and are not extruded.  Oxygen utilization is efficient and used for ATP production, which in part is in contrast with phagocytic cells, wherein some of the cellular oxygen is directed at “oxidant” and superoxide production.  The point here is that interpretation of results related to cell signaling is cell-type and process dependent.  When the only data available are derived from cells in culture, it ‘s hard to make assertive conclusions without a lot of nuance and other assumptions.

mTOR, PQQ, and Muscle

So – can mTOR levels influence muscle growth.  The answer in some situations is yes.  Several research groups have noted that there is a sarcopenic effect (presence of lower muscle mass and either lower muscular strength or lower physical performance) with long-term mTOR inhibitor use (e.g. for long-term cancer treatment. (cf. Gyawali et al. Muscle wasting associated with the long-term use of mTOR inhibitors. Mol Clin Oncol. 2016; 5:641-646).  Importantly, only very very potent mTOR inhibitory agents have been studied.  Thus, to what extent this has a direct relevance to a normal exercising person taking PQQ is not clear.  Moreover, as it relates to PQQ, there are few comparative studies of using differing cells and their response to PQQ exposure.  We know of only one.   Min et al. reported (J Cancer. 2014; 5:609-24, https://www.ncbi.nlm.nih.gov/pubmed/25161699)

PQQ exposure enhanced apoptosis (programmed cell death) in tumor cells (3 types of tumor cells were studied) but promoted no apoptotic changes in the normal cell lines derived from renal and umbilical-derived cells.  Accordingly, an answer to the PQQ/muscle question is, if there is an effect, it is probably modest, if at all.  Importantly, exercise “trumps” most known dietary factors and nutraceuticals taken as supplements to optimize muscular function or maintenance.

As a final comment, for questions such as the one posed, going to the resveratrol literature is sometimes helpful.  In many respects PQQ and resveratrol (RV) influence similar cell signaling pathways.  A PubMed search identified over 50 papers addressing RV, tumor growth, and apoptosis, i.e. RV suppresses tumor growth.  In contrast, there are dozens of paper suggesting RV improves many aspects of muscle function.  For PQQ, although the literature is not as extensive, the available reports suggest similar findings.

Summary

In an active individual, is PQQ going to do much independent of the effects of exercise?  Few external factors promote muscular or mitochondrial function as well as exercise itself.  The mTOR cell signaling pathways are clearly essential to muscle function, but any mTOR inhibitory response that PQQ might have is probably overridden by other factors.  For example, PQQ has been shown in animal studies to have clear positive effects on neonatal growth, anti-ischemic/cardio-protective effects, neural protective effects, an ability to enhance fatty acid metabolism via mitochondrial oxidation, and anti-inflammatory effects.  Rather, than increasing performance per se, the benefits of PQQ, if any, are more likely related to recovery following an episode of intense activity.  In this regard, some mTOR suppression may have some utility.