We talked about the differences physiologically
between males and females, and we talked about
how the fiber type, you know, fiber sizes are
different, but also the proportions, right? And
how those proportions then influence metabolism
is huge. So if you have more type two fibers,
which is what we see generally again in males,
generally depending on training status, then
you're going to have more glycolytic pathways,
which is reliance more on carbohydrates. When
you have more oxidative fibers or type one fibers
in females, you're going to have more capacity.
to utilize fats as a fuel. Hi, Shani. It's my
pleasure to have you on Evidence Strong Show.
If you could briefly introduce yourself. Hi,
Alex. Thanks so much for having me. So my name
is Shani Landon. I'm a postdoctoral researcher
at the Hudson Institute studying genetics and
physiology. Other than research, I also compete
over 800 meters. So it kind of gives me an extra
interest in understanding how our bodies work
when we adapt and when we exercise and having
a kind of molecular explanation for that. That's
perfect. The paper you just published is titled
Physiological and Molecular Sex Differences in
Human Skeletal Muscle in Response to Exercise
Training. Let's start with the most obvious and
burning question, which is what are the differences
in physiology between females and males? If you
kind of break it down into the different organs
or the different tissues that we have. So males
tend to have larger hearts, which means then
larger stroke volume. higher cardiac output,
that males have larger lungs and cross -sectional
areas of their conducting airways. Males have
more... hematocrit and hemoglobin in their blood
cells and more hemoglobin mass, stronger bones,
more dense, and with what it means for muscles
then and for adipose tissue. So males have a
higher proportion, and I'll talk a bit more about
this and kind of how this links in to the sex
differences that we discussed in the paper, but
males have a higher proportion or tend to on
average of type 2, so the fast twitch glycolytic
muscle fibers, while females, again, on average,
and it depends on training status, will have
a higher proportion of the type 1 or the slow
twitch muscle fibers, the oxidative ones. With
adipose tissues, there's a different distribution
of fat between males and females with also males
having relatively less fat percentage. So a healthy
male on average versus a healthy female. on average,
males will have less fat. And that kind of sums
up the components of the organs that we would
think about when we're thinking about physiological
performance. And what that then contributes to
is males, quote unquote, outperforming females
or having higher personal bests by 10 to 30 percent,
depending on the event. And that will then contribute
also to strengthen many different aspects. So
in females. relative strength between the upper
body and the lower body is that females have
more relative strength in their lower bodies
compared to their upper bodies while that phenomenon
does not exist in males so that just means you
know if you're if you're squatting more as a
as a female and not able to do as much bench
press like there's potentially a bit of a physiological
explanation for that and then that the relative
between males and females is that again on average
the males upper body strength is 157 percent
of the females upper body strength and for the
lower body strength it's about 60 percent more
so that just shows you that the discrepancy is
much greater in the upper body between males
and females than it is in the lower body so yeah
despite those differences in in strength and
the capacity males and females still from what
studies have shown are able to increase their
strength to the same degree and so respond and
adapt to the same degree and that the differences
in strength between males and females tend to
appear more due to the muscle mass rather than
the force generating capacity of each unit. So
it's just the fact that there's more muscle fibers
and they're bigger that can produce more force.
What are the molecular differences we know about?
So I kind of think about this is that there is
multiple levels of kind of the molecular profile.
So you have, we'll go through the central dogma
just to... The central dogma for genetics is
that you have... DNA, which is the same in every
single cell of your body, essentially. And that
DNA then so gets transcribed into mRNA. the messenger
RNA, and that will be different between different
cells, between different tissues. And that mRNA
then gets translated into proteins and proteins
go on to have their function within the cell
and to communicate between other cells. There's
then several layers of what we call gene regulation.
So basically impacting which genes, so the DNA
component, in the end get translated into proteins.
And there's kind of many steps in which you can
affect that process. So one of the ones that
we looked at, which is type of... epigenetic
modification. So epigenetic is kind of how our
genes are interacting with their environment,
with the environment in the cell. And that can
come from a lot of different factors. It can
be our diet, it can be our exercise, our sleep,
the different toxins that we have that can interact
with our DNA. And they don't change the sequence,
but they tag on different things onto the DNA.
So one thing that can get tagged on is what's
called a methyl group. So then it's called DNA
methylation because a methyl group gets tagged
onto the DNA that then determines how tight or
how open the DNA is. And that can then decide
which genes get then transcribed into the mRNA.
Then we have another process that is the microRNAs.
And that's different than the mRNAs in that the
microRNAs will find an mRNA and they'll say,
oh, we're going to go attach to that one and
degrade it. So that then influences how much
mRNA is present in the cell. So that's another
level. And then there's other levels of gene
regulation that I won't go into. into because
I won't talk about them today, but there's other
components as well. So it's not so, you know,
it's just those two. There are different levels
in which the DNA then gets decided how much protein
of that gene is left in the cell at the end,
if that makes sense. Okay. So in your study,
you took biopsies of females and males and you
check what is the state of molecular translation.
in these cells, including the effect. So including
the final product, the proteins that were produced.
Yeah. So the first thing we wanted to do was
to just see at baseline, what are the differences
between males and females in the muscle? Because
at the time it was not even ever looked at or
known if DNA methylation even differs between
males and females in muscle. It had been shown
in blood, it had been shown in some other type
of cells, but not in muscle. And then same thing
with proteins. We didn't know on a kind of global
level. So when I say global, it means that With
our methodology, we used high -throughput methods
that are now very common practice, but it's technology
that's come out in the last couple decades or
decade or two, and they basically allow you to
look at... all of the proteins or, you know,
thousands and thousands of genes at one time
when it comes to DNA methylation as well. So
it gives you kind of a genome wide is what we
call it, or a picture of kind of everything that's
going on in the muscle. And because those methodologies
have, you know, developed over time, I say they've
been around for a decade or two, but that's kind
of like, it depends on which component we're
looking at. And also the development with it
has meant that it's become a lot more sensitive,
a lot more accurate in the quantification. So
what we were able to see is that that just at
baseline, before anyone does any exercise, there
are thousands of genes that show different methylation
in the muscle between males and females. And
that then means that we expect them to have differences
downstream, right? Differences in the mRNA, that
was already known at the time. mRNA is kind of
the most advanced in what technology has been
around and for how long. And so it was already
known that there are differences at baseline
between males and females in skeletal muscle
and their gene expression or their mRNA. And
then with the proteins, we also found that just
at baseline before exercise, there were several
hundreds of proteins that were. differentially
expressed between males and females. So the functional
unit protein at the end, if you just look at
a male muscle and just look at a female muscle,
you can tell who it came from because the protein
profile was very different. So that was to start
it off going, okay, before we even exercise,
how different are they? Yep. Very different in
both of those aspects. And then we looked at
what happened after four weeks of high intensity
training. So that was all on a bike and it was
all monitored to make sure that they're going
at a certain percentage of their BOT. max and
a certain percentage of their lactate threshold
and it was it is quite um like they're hard workouts
but of course we also had people that came in
with different training statuses so you could
have been kind of an untrained individual to
a pretty fit individual so that will also kind
of you know it was a limitation within our study
because it will increase the variability of our
results and potentially impact the findings but
in general you know we were able to control for
their vo2 max level so that was kind of taken
into consideration in our analysis but in any
case what we found was that the proteins changed
substantially after four weeks of training in
the muscle, and they changed differently between
males and females. So if you're a male, you know,
those proteins changed in that direction. And
if you're a female, then different proteins changed
in different directions. So that's what we found
with the proteins. And then with DNA methylation,
what we found, which was surprising to me at
the time, or not what I was expecting, was that
there wasn't a huge effect of exercise training
on the DNA methylation status. It was slight
but not much and there was no difference between
males and females. It's like yep it changed a
little bit and what we can see looks the same
for males and females. Okay so then I we got
to thinking if that's what happens with four
weeks which is you know a small amount of time
to be training and we know you know what what
adaptations lifelong training will bring are
going to be a lot more robust then We wondered,
what about the cardiorespiratory fitness of these
individuals? Because we had such a range and
everyone performed VO2 max tests before and after
they started, then we kind of had a fitness level
for each one of them, which indicates lifelong
training, cardiorespiratory fitness, right? VO2
max is a good measure of those. So we then used
VO2 max to kind of give each individual a value,
like this is how fit they are. The VO2 maxes
ranged from about low 20s to we had some very
fit individuals that were like mid 60s. We had
quite a range and we had a lot of individuals
as well. There were 20 females and 45 males.
So for these muscle biopsy studies, which are
kind of hard to get people to necessarily agree
to give a piece of their muscle, it's relatively
a decently sized study for this kind of endeavor.
So yeah, what we found was that these fitter
individuals, people with higher VO2 max, had
a very different profile in DNA methylation than
unfit individuals. So that indicated that...
lifelong training or your cardiorespiratory fitness
influenced the DNA methylation profile in the
muscle. And it wasn't different between males
and females, which again was very interesting
to me. It was like, if you're fit, this is what
your profile looks like. Doesn't matter if you're
a male or female, even though there's baseline
differences. And I can get to that in a second.
And then what was also surprising to me is that
we didn't find the same with protein. So in proteins,
we didn't see any effect of lifelong training
on the proteins. So that was an indication to
us that doing, you know, an acute bout of training,
right, four weeks will potentially. affects more
the proteins right it has more of an acute effect
but that lifelong training which is more you
know everything that's happened in your whole
life like your cardiorespiratory fitness is more
affecting your dna methylation that acute training
was having a more substantial effect on the proteins
while the lifelong effect has more of an effect
on dna methylation which is more of a of a stable
process so proteins can really like fluctuate
with depending on what you eat and what you do
but that potentially the DNA methylation is more
transient and takes more time to change. And
so we were kind of able to see that in both ways
because of what we saw after four weeks and because
of what we saw when we looked at the association
between VO2 max. So since then, I mean, it was
a really interesting finding to me to think that,
you know. your VO2 mocks or the training that
you've done your whole life influences, you know,
something really deep in the cell, you know,
the DNA methylation of the cell, which it can
change and is malleable, but... it's less transient
than the proteins. And so since then, we've completed
another study, which meta -analyzed other studies.
So basically said, okay, we have our 65 individuals.
We have some limitations in our studies. And
since then, a lot of other studies had come out
that had taken muscle biopsies and done VO2 max
for those individuals. They didn't necessarily
look for sex differences, but we were able to
mine their data and meta -analyze it with ours.
And we were able to confirm everything that we
saw in our... study, which was, which is always
comforting in science when what you found is
replicable and, you know, you're not the only
one who reached those conclusions. So being able
to do that and replicated in those other cohorts
really strengthened, you know, what we, what
we saw, which is that, yeah, the differences
between males and females were evident at some
levels of gene regulation and not others. And
that exercise training had a strong effect on
the proteins early on, but later on with sustained
training, more effect on the DNA methylation
status and the muscle. were kind of our main
findings. And microRNAs, we didn't go as much
in depth as this, but we also found that the
microRNAs changed differently between males and
females after exercise. That was with an acute
bout, not with the four weeks. It sounds like
ventilation is important. And it's early in the
process of a transcription. So potentially the
impact is bigger, especially in the long run.
This is something that the cell has to kind of
plan in advance and put an effort to put methylation
at the beginning of the process of transcription.
And then things are happening. At the end, we
have proteins. So with acute exercise, it seems
like the end of the process can be manipulated
pretty quickly. But the methylation part, maybe
because it's... earlier in the process, maybe
it requires more from the body to be put in place.
That's why it's affected slower. Am I close?
Yeah, I think that that's kind of the idea that
I have in my mind is that it takes longer to
have those effects because it's a more intricate
process. With proteins, we know that you can
break down, you know, you have protein degradation,
your protein synthesis, it's like a quicker,
faster acting process. With DNA methylation,
it requires, you know, a bit more of kind of
setup. by the other proteins in the cells that
need to interact to then tag that on. And then
it's going to take time until, you know, everything
kind of flows downwards from that. I say time,
everything in our cells happens pretty quickly.
But yeah, essentially it is higher up the chain.
It's like if you think about you have a boss
at the top and if you want to get something happening
and changing quickly at the bottom, if you get...
to send a message to the boss and wait for how
long it takes to get to the bottom of the chain,
that's going to take a while. But if you tell
the person at the bottom straight away, then
that's going to be much quicker in its effect.
Oh, I like it. Okay, so the methylation is important.
I'm trying to gauge whether it's a good thing
in relation to exercise and adaptation and performance.
Is it a good thing or bad thing? Do we want more
of it or less of it? Or is it just that it has
to be in specific places? How should we think?
about it yeah definitely in specific places so
it's gotten really big now to look at the effect
of aging for example on dna methylation there's
it's a really hot topic right now and it's something
that my previous lab worked was working on a
lot as well and that i've been involved in and
what we kind of see is that aging has one effect
on dna methylation and exercise has the opposite
effect on those same sites so it's like you have
increases or decreases globally, yes, but it's
more specific to the sites that it's at and it's
having its effect. So there's some genes that
increase with methylation with age and with exercise
and others that decrease depending on the location
in the gene. We know from from other studies
that there will be differences in how resistance
exercise or endurance exercise impacts our molecular
profiles in our muscle. I don't think that there's
been enough studies out there for us to have
a very clear conclusion on what kind of changes
are different if you do strength training or
endurance training and how that impacts DNA methylation
differently. Maybe there's something that's come
out that I'm not aware of, but from what I know,
there hasn't been a direct comparison to see
the differences. between those two training modalities,
whether frequency and duration. I mean, we know,
you know, with exercise training adaptation,
it's all about intensity, frequency and duration.
So we can kind of presume given that. the changes
that we were seeing were associated with VO2
max, then that kind of has intensity, duration,
and frequency within it, right? So the more that
you exercise and the higher VO2 max is, that's
where we saw that strong signature, that strong
DNA methylation signature. So I would say, yeah,
of course, it's the more intense and the higher
that it is, the more that you're going to have
this effect. And that's where we're seeing the
impact on the DNA methylation. And whether there
are other things that influence... our DNA methylation.
Yeah, I mean, it's kind of a very blanket term
to how our genes are interacting with the quote
-unquote environment or their environment. So
there's a lot of different molecules or factors
that will float around in our cells and impact
which genes are methylated higher or lower. And
things like smoking have a really strong effect
on DNA methylation. Like we said, exercise. I'm
trying to think what other studies have shown.
A strong cancer disease. the things that are
happening in our cells are very much influencing
our DNA methylation. And what's it to a pot?
You asked what's impacting our DNA methylation
in a positive way. I mean, define positive. If
you want it to look more like exercise, is that
positive? If you want it to look less like aging,
is that positive? I think it gets a little bit
of a cloudy in that sense. But yeah, we do know
that the things that we do, the toxins we're
exposed to also influence DNA methylation. But
yeah, the main ones that have been studied and
have been robustly shown are aging, smoking,
cancer and disease, toxins. Now, yeah, exercise
as well. I guess I could just add it wasn't in
our study because it was already known that,
yeah, I think I did mention it, but that there
are thousands of genes that are at the mRNA level
also different between male and female skeletal
muscle. And there was a good made analysis that
came out a few years ago that I can also link
in the notes by another group that looked at
all the studies out there that performed fossil
biopsies and had males or females and trained.
And they also saw that the mRNA were also changing
differently after. exercise, whether you're male
and female. And there, I think they did group
on different exercise modalities, if I remember
correctly. So that could be your previous question
as well with comparing the different exercise
modalities, at least at the mRNA level. We didn't
look at the other, I don't know of other studies
that have looked at the other levels, but they
did compare how, jumped on another point of another
important level of the central dogma, which is
the mRNA, and that there have been a lot of studies
on looking at the mRNA changes with exercise
training. And there was a good meta -analysis
that came out a few years ago that basically
found all the studies that took muscle biopsies
before and after training and looked and saw
if there was a sex difference. And they did see
that there were hundreds of genes that changed
differently between males and females in muscle.
So the mRNA level before and after training.
And they did include different training modalities,
I think. So they also had endurance and strength
and made that direct comparison. So before what
we talked about, we don't have a direct comparison
from what I know of the DNA. and methylation
changes and if they're different between strength
and endurance. But we do know about mRNA levels
changing differently depending on the training
modality. And so, yeah, I can link that in the
link. Send you that link as well if you want
to put it in. That would be awesome. So is it
that we can see if we take genetic material from
skeletal muscle of a person, random person, we
can guess whether they are athletes or not and
potentially what type of sport they are doing?
I thought you were going to ask about the male
and female aspect because that part's super interesting.
There's actually a really cool paper that found.
That's my next question. Next one. So I'll answer
that one first just because it's more definitive
of an answer. And I think it's fascinating. But
a paper that came out a few years ago tried to
predict if we look at the mRNA in a tissue, can
we predict if it's male or female? And they knew
if it's male or female. So they could check if
the prediction was right. And they found they
looked at all the tissues, you know, 40 something
tissues in the body. And it was with it's using
what's called the GTEx portal. So it's. It's
a large publicly available data set that has
hundreds and hundreds of people that have donated
their tissues after they've passed away. And
so it's quite robust, the findings. And they
found that besides breast tissue, skeletal muscle
predicted sex the best out of any other tissue.
So that just shows you, yeah, just how that's,
you know, we call skeletal muscle one of the
most sex -biased tissues in the sense that it
really is differentiated between males and females
compared to, you know, brain tissue, liver, kidney.
any other tissue that was that was in there so
yeah which makes sense giving given how hormone
responsive it is and that the hormones will really
differ between males and females and i had a
whole bit i was gonna explain to you about hormones
versus genetic yeah so that's to answer whether
muscle can differentiate i mean we can differentiate
based off of muscle if it's males and females
and whether we can differentiate their training
status that that's a really good question maybe
that's a future paper that we work on absolutely
because yeah there's lots of kind of machine
learning algorithms out there to try to predict
those things. And if we had the VO2 max of those
individuals, if we were able to predict how fit
they were. Yeah, that's an awesome question.
I'm going to steal that. Let's see if there's
a student that wants to work on that. That's
awesome. We have to know if we can predict pretty
robustly whether the tissue, the muscle tissue
is from a female or from a male. Why? Why they
are so different? What is happening from the
genetic point of view and then through physiology?
that we end up with so different tissues. So
that's something that I tried very hard to answer
during my PhD and in my thesis and was limited
in my ability to answer that because typically
females have XX sex chromosomes, so two X chromosomes,
while males will have XY chromosomes. And that
then sets up many differences in our cells, in
our DNA. And what I mean by that is, so that's
kind of the first difference that we see, you
know, at day zero, at conception. The embryo
is either XX or it's XY. And if everything goes
kind of typically and there's no variations to
the sex development process, which is the lab
that I work in now, is very focused on sex development
and on the different variations that happen to
this process. And I can speak to how that kind
of relates to my previous work as well. But those
first differences are going to set you up for
all the differences that come up. come downstream.
So if you have XX or if you have XY, it basically
takes your gonad development. So we start with
a bi -potential gonad, which means it has two
potentials. It can go on to be ovaries and it
can go on to be testes. And you need to have
a few key players present or absent in order
to kind of go down those two pathways, one of
those two pathways. And so having XX, if everything
goes normally, will then develop into ovaries,
which then means you have high estrogen, high
progesterone, and lower testosterone levels.
Or if you have XY, that typically will take you
down the other pathway in which you develop testes
and you have higher testosterone relatively and
lower estrogen and progesterone. And so then
there's kind of then thought of as two main drivers
of the sex differences that we see. So everything
that we talked about until now, the performance,
the physiology, the proteins, the gene regulation.
It's thought that those two are driven by those,
that those things are driven by those two components.
The difference, the fact that you have XX and
XY and the fact that you now have different hormone
levels for the rest of it. your life. And those
two things will impact what goes on in the cell.
And so it's kind of impossible to break apart
those two drivers because they come together,
right? If you have XX, you have that hormone
profile. If you have XY, you typically have that
hormone profile. So how will you say if the difference
that you see is due to having different sex chromosomes
or different hormone levels? Because while they
come together, you can't break them apart. So
that's what a big project that I'm currently
working on in the lab that I'm in now, which
is that the lab that I work in before I came
in developed in collaboration with a couple labs
in the U .S., what's called a four -core genotype
model. So it's a model that's existed in mice,
again, by our collaborator at UCLA for over 20
years. And when I came in, they had just finished
producing a rat version of this model. And what
this model is and why it's called the four -core
genotypes is that we end up having four genotypes.
One that's, you know, a typical XY male, a typical
XX female, but then we have XX males and XY females.
And what that allows us to do is to break apart
the impact of the sex chromosomes and the hormones,
because now they're not linked together. Shani,
just to make it clear. So when you say XX female,
that's XX genetics and female hormonal profile.
If you say XX male, you mean XX genetic profile,
but hormonal profile is the profile of a male.
Is that? Exactly right. Yeah. Yes. So when I
say male or female here, it just is describing
phenotypically or the gonads. The moment the
gonads are testes, have high testosterone. The
moment the gonads are ovaries, you have high
estrogen. So yes. So yeah, that model has been
used in mice for decades now to understand the
drivers of a lot of different sex differences.
So one, for example, is that what was found is
that the X chromosomes are what strongly influence
adiposity. So animals that had two X chromosomes,
regardless of their hormone levels, were fatter
and ate more. And so it was kind of a, you know,
revelational in the sense that, you know, we
see so many of the differences. It was commonly
thought that so many of the differences that
we see between males and females are due to hormones.
And we know that hormones have such an influence
on fat cells and on adipose tissue. But yeah,
that study had kind of shown that there's also
a role for the genes that are on the X and Y
chromosomes that's been previously underappreciated.
So there are a lot of studies. that have come
out showing there's a specific gene on X or a
specific gene on Y. that can influence a specific
trait or a specific disease. And so, yeah, it's
understanding that there's also now this level
of, well, if you have two X chromosomes, it means
that you have a different level of genes expressed
in those chromosomes if you're a female. And
if you have an X and Y, then you have different
genes there as well in a male. So there's those
inherent differences. So you asked, you know,
to bring you back to the exercise adaptations
and what we were seeing. I tried my best to answer
that question with the human data that we had,
which is, well, those two things are linked.
can't really pull those components apart. We
did as much as we could. And we did see that
if you looked just within females, and we did
have all their hormone levels measured in their
blood, their testosterone, their estrogen levels,
their SHBG, we all measured. And we did see that
within females, because again, we couldn't compare
males to females without. having those two things
intertwined, right, the genetics and the hormones.
But within females, we saw that hormones were
impacting the DNA methylation level, so the level
of hormones. And I mean, there's not a great
variability in testosterone within the female,
so that's not a huge finding. But with estrogen,
you know, and it's really variable because it's
changing throughout the cycle and it will be
different between people. And while we did collect
blood and muscle from people always in their
early follicular stage, so the first seven days
of their cycle, to try to minimize that variability,
there will. inherently be variability because
that wasn't also the goal of the study so it
wasn't you know super tightly controlled as it
could be it was just as tightly controlled as
we kind of needed it for the bigger question
but that yeah we do see that hormones influence
the DNA methylation levels preliminarily from
what we found but that further work is needed
which is kind of what my lab is working on now
in collaboration with with another lab is to
understand what is driving the sex differences
in the muscle and I can tell you what we found
so far I'm still preparing that manuscript and
don't have super firm conclusions yet. But what
I'm finding so far that's really interesting
is that there is a really strong effect of the
gonadal hormones, so the testosterone, estrogen,
progesterone, on the mRNA levels in the muscle
of these rats. But there is still some component
that's influenced. by the sex chromosomes. So
we've kind of looked at a bunch of different
tissues and tried to see, okay, what's having
an effect in the mRNA levels in these different
tissues? Is it the sex chromosomes or is it the
hormones? And for most of the tissues, it's been
the hormones, but not for all. And muscle is
one of the ones that hormones seem to be having
a much stronger effect. But again, that there
is still some effect of the sex chromosomes,
which is super interesting. And we're still going
through kind of each gene, each mRNA and seeing,
okay, what's... this one? What's its function?
Why is this one driven by hormones? Why is that
one driven by the sex chromosomes? So we're still
kind of piecing that together. And the best that
I could kind of do in my PhD with the human data,
because again, that was rat data. The best I
could do in my PhD with human data was to kind
of see if there's hormone responsive sites around
the DNA methylation differences we were seeing.
And we did see the androgen receptor was nearby.
those sites, which indicates that likely there's
a kind of a hormonal explanation for some of
the DNA methylation. differences that we were
seeing in the human muscle. If we know that there
are differences between females and males, and
some of the differences are due to genetics,
some of them are due to hormones. If there is
any relation between how hormones influence genetics,
I would be interested to know. Okay. Yeah. I
mean, I think it's a fascinating topic, so I
kind of had it in here. So how progesterones,
estrogens, and testosterone work is there's kind
of two signaling pathways, but I'll focus on
the main one. and the one that's kind of the
most canonical one is that hormones have receptors.
We have testosterone that's floating around the
cell, in the cell, and it needs to bind its receptor.
That's how it exerts its action. And when it
finds its receptor and they're together, they
then enter the nucleus where the DNA is held.
And that receptor can either directly or indirectly
bind the DNA at specific sites. So there's specific
what are called hormone responsive elements.
So different sequences that will say, okay. We
recognize when there's an androgen receptor and
it will bind here and it will then directly impact
which genes get transcribed. So which mRNA then
come out from that interaction. So that's how
hormones are really directly or, you know, we
say indirectly because there's sometimes other
proteins that are involved, but we can say directly
or indirectly changing which genes are getting
transcribed into mRNA. So that's kind of how
hormones exert their effect. And yeah, so basically
they're kind of seen as what we call transcription
factors because they are a factor, right, in
transcription. They can bind the DNA. The receptors
can bind the DNA. What the future is bringing.
Yeah, I think with every scientific question,
the moment you answer it, you just kind of come
out with more questions. So there's always more
questions to answer. A few that I kind of had
left after our work or with our work so far.
A big one is the influence of the fiber types.
So I didn't really, you know, I didn't go into
this. I probably should have and is more interesting
to your audience than all the molecular details
that I gave. But I will add in that maybe you
want to put it in earlier on, but it's not really
a summary. It's something I meant to mention.
I just realized. is that what we know about,
and we talked about the differences physiologically
between males and females, and we talked about
how the fiber type, you know, fiber sizes are
different, but also the proportions, right? And
how those proportions then influence metabolism
is huge. So if you have more type 2 fibers, which
is what we see generally, again, in males, generally
depending on training status, then you're going
to have more glycolytic pathways, which is reliance
more on carbohydrates. When you have more oxidative
fibers or type 1 fibers in females, you're going
to have more capacity to utilize fats as a fuel.
So it has been shown multiple times that in endurance
training, females will have a bit more of a reliance
on fats as a fuel while males will have a bit
more of reliance on carbs as a fuel of course
they're both relying on both throughout training
but the shift is a little bit different given
that we have different fiber type proportions
right type one versus type two within a male
muscle or within a female muscle so that then
is a huge question left to answer with what we've
seen. So are all the differences that we're seeing,
you know, in DNA methylation, in proteins, in
mRNA, is that all partially or very largely driven
by the fact that we actually have different distributions
of type 1 and type 2 fibers? And again, I tried
to answer that as best as I could because we
did check for the fiber type proportions in all
of the individuals, the 65 individuals that we
had in our study. It's the data I was analyzing
the night before my wedding. But anyways, no,
I won't get into that. Yeah, so that's... a huge
question left to answer is, you know, how much
fiber types are influencing the molecular profiles
that we see. And it's something that a colleague
of mine did his PhD on after I completed my PhD.
So he has some papers coming out on that. And
that work is still ongoing. Preliminarily, or
what he's finding so far is that there is a component
of the proteins that is largely impacted by the
fiber type differences between males and females,
which is also what I was finding in DNA. that
there's a really strong signature of DNA methylation
in type 1 fibers or in type 2 fibers with, again,
the limited ability of my study to answer that
question because it wasn't designed for that.
And there have been studies out there showing
just how different the kind of molecular profiles
are, right, the proteins and the DNA methylation
and how they are different between type 1 and
type 2 fibers. So that's a big part to take into
consideration with things left to do. Another
part, which is what we touched upon, which is
what's driving those differences. which can be
answered in multiple different ways. One is what
we're trying to do with the RAP model. The other
is using, indeed, gender -affirming hormone therapy
individuals and seeing what hormones will do
to their muscle. And yeah, there's kind of a
few different ways we could try to answer that
question. And the other thing is really just
understanding the different levels of gene regulation,
because that'll paint a bigger... kind of more
comprehensive picture of what is happening with
exercise adaptations. And, you know, if we were
seeing differences between males and females
on protein level, but not at DNA methylation,
and we're seeing it at mRNA, what's happening
with everything in between? Like what is the
mechanism behind it? And while we tried to answer
it, you know, in a few different ways, it's as
we kind of hopefully alluded to is pretty complex.
And there's a lot of different players. There's
a lot of different. ways to regulate which proteins
end up at the end of the day having their function.
So kind of at which level is everything happening?
Where is exercise exerting its effect? Where
are the sex differences coming in? Are they earlier
on? Are they later? Are they across the whole
process? Yeah, just the complexity of the gene
regulation, I think, is still a lot of questions
left to answer there. That's awesome. Thank you
so much for sharing what we know so far. Let's
finish with some advice for coaches. So if you
could bring it all together and compress it,
would you have anything to say that coaches should
know about the differences between female and
male muscles? I think a better understanding
of... what is going on in our bodies and our
muscles, you know, contributes to a better understanding
of kind of how to, how things work. I don't know
how you want to think about. life and training.
And I mean, other than the kind of basic ones
that we know, which is, you know, females have,
you know, greater relative lower body strength
and upper body strength. And I don't know if
that's something to take into consideration when
you're planning, you know, your load and the
rep, you know, the load that you're aiming to
hit for your different reps. I think a lot of
it also comes down to practice and to individual
experience. And I think while, you know, every
individual is going to be different, we're looking
at males and females as a whole. But of course,
there's so much individual variability as well.
So it's hard to kind of have these concrete conclusions
on this is what you now should do. But I think
it's just the more we can understand what's happening
molecularly, the more we can just get a bigger,
more clear picture of, you know, what exercise
adaptations are looking like. And, you know,
what is that lactate burn at the end of 400 meters?
You know, what does it mean on a molecular level?
Yeah, regarding looking at males versus females
and how to really take that into consideration.
A few examples come to mind, like, you know,
I think males tend to have a larger difference
between their first and second lap in an 800
meters. All right, you run and then you get really
tired and continue running and you slow down
a bit. Males tend to slow down more compared
to females, which in my molecular mind makes
sense, because if we know that females tend to
rely more on fats and kind of have relatively
enhanced endurance compared to males in the sense
that, you know, they're able to. kind of rely
on that process more then it kind of makes sense
to me that they're able to run a more even pace
right and more if you're relying on fats and
your oxidation then you're relying more on your
endurance capacity so you're going to be a bit
more even when you're thinking about males in
the 800 and if it if you're slowing down then
you've relied a bit more on speed to get you
there and then you've slowed down you know so
it's kind of hard to put into I feel like I didn't
explain that really well. But what I'm hearing
is that females run slower in general than males,
but they are able to keep the tempo better because
they are slower, probably because of the same
reasons that they are able to hold the pace.
So the genetics are different. The muscle mass
is different. The fueling is different. Exactly.
And there are also some mental, you know, females
and males mentally are a little bit different
too. And there are some factors in the sports.
that will benefit potentially from that too.
So lots of things, very complex, but I get where
you're going with it. Yeah, yeah. I think depending
on the exercise that you're interested in or
that you're doing or that you're involved in,
you can potentially think about the different
components of this in different ways. So my head
goes to that and realizing that those are some
of the differences we see in the 100 between
males and females is the pacing. And that can
kind of be explained by... the understanding
of the metabolism and the molecular components
of it. So yeah, depends on what you do. And then,
you know, same with strength. If we're looking
at upper versus lower body strength, then it's
another. thing to understand yeah in that sense
is the best way i can kind of think of how to
relate this to practice beautiful two short questions
to finish the first one is what is your favorite
exercise you already said 800 yeah i was gonna
say i don't think i should not stray away from
that but yeah if you were to ask me like my specific
the 800 is a delicate combination between endurance
and strength so kind of get to do everything
from speed training to speed endurance to endurance
to to strength you know power strength training
so a bit of everything which I love that aspect
of it. Probably my favorite workouts is like
200 meter hill repeats. There's just something
to making it to the top of the hill. You know,
you and your glutes are on fire and just you
feel on top, you know? So yeah, it's probably
my favorite workout. And the last question is
where people can find you online if they want
to follow your work and learn more. I'm not the
most active. I do have LinkedIn. So if you just
search my first name and last name, I'm the only
one. But yeah, so I'm trying to post. more and
get more exposure to our work. So through LinkedIn
would probably be the best way. Thank you, Shani.
It was a pleasure.