162
Molecular Insights From Multiomics Studies of
Physical Activity
Wei Wei,1,2 Steffen H. Raun,3 and Jonathan Z. Long 1,2,4,5,6
Diabetes 2024;73:162–168 | https://doi.org/10.2337/dbi23-0004
Physical activity confers systemic health benefits and
provides powerful protection against disease. There has
been tremendous interest in understanding the molecular
effectors of exercise that mediate these physiologic
effects. The modern growth of multiomics technologies—
including metabolomics, proteomics, phosphoproteomics,
lipidomics, single-cell RNA sequencing, and epigenomics—
has provided unparalleled opportunities to systematically
DIABETES SYMPOSIUM
investigate the molecular changes associated with physical
activity on an organism-wide scale. Here, we discuss how
multiomics technologies provide new insights into the sys-
temic effects of physical activity, including the integrative
responses across organs as well as the molecules and
mechanisms mediating tissue communication during exer-
cise. We also highlight critical unanswered questions
that can now be addressed using these high-dimensional
tools and provide perspectives on fertile future research
directions.
Regular physical activity can help reduce the incidence of
obesity and obesity-associated metabolic diseases (1–3). In
contrast, physical inactivity has become increasingly com-
mon in the U.S. population (4), representing a significant
modifiable risk factor for cardiovascular diseases, obesity,
diabetes, cancer, and overall mortality (5,6). Understand-
ing the molecules and pathways involved in physical activ-
ity’s cardiometabolic benefits has garnered significant
interest (7). This understanding serves as a crucial first
step toward developing future therapies that could poten-
tially harness the health benefits of exercise.
Historically, molecular studies of physical activity have fo-
cused on specific molecules in individual metabolic tissues,
1
Department of Pathology, Stanford University School of Medicine, Stanford, CA
2
Sarafan ChEM-H, Stanford University, Stanford, CA
3
Department of Biomedical Sciences, University of Copenhagen, Copenhagen,
Denmark
4 This article is part of a special article collection available at https://diabetesjournals
Stanford Diabetes Research Center, Stanford University School of Medicine,
Stanford, CA
5
Stanford Cardiovascular Institute, Stanford University School of Medicine,
Stanford, CA
6
Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA
Diabetes Volume 73, February 2024
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such as muscle, adipose tissue, liver, and pancreas. In the
past decade, advancements in multiomics technologies—
including metabolomics, proteomics, phosphoproteomics,
lipidomics, single-cell RNA sequencing (scRNA-seq), and epi-
genomics—have offered unparalleled opportunities to ex-
tensively investigate the molecular changes associated with
physical activity at an organism-wide scale (Fig. 1). Numer-
ous exercise “omics” data sets start to emerge (8,9). These
data sets provide a high-dimensional and detailed view of
the molecular processes involved in exercise, further refining
our understanding of the molecular events related to this
complex physiological stimulus. Simultaneously, the vast
amount of data generated with these modern techniques
have raised new questions and opened up potential avenues
for discovery regarding the molecules and molecular mecha-
nisms underlying physical activity’s beneficial effects.
In this article, we will focus on the latest develop-
ments using multiomics approaches to explore the mol-
ecules of physical activity. We begin with a discussion
of how multiomics technologies have provided new in-
sights into the systemic effects of physical activity, in-
cluding the integrative responses across organs and the
molecules and mechanisms mediating tissue communi-
cation during exercise. We also discuss multiomics studies
that revisit the classical exercise-responsive metabolic tis-
sues, including muscle and adipose, and how these studies
have extended our understanding of the responses of
nonparenchymal cells, including immune cells, to physical
activity. Lastly, we share our perspectives on the future
directions for multiomics technologies as applied to exer-
cise research.
Corresponding authors: Wei Wei, wwbiomed@stanford.edu, and Jonathan Z.
Long, jzlong@stanford.edu
Received 10 April 2023 and accepted 4 June 2023
.org/collection/1824/Diabetes-Symposium-2023.
© 2024 by the American Diabetes Association. Readers may use this article
as long as the work is properly cited, the use is educational and not for
profit, and the work is not altered. More information is available at https://
www.diabetesjournals.org/journals/pages/license.
diabetesjournals.org/diabetes
Figure 1—Overview of multiomics technologies for investigating the complex molecular response to physical activity.
MULTIOMICS OF INTEGRATIVE EXERCISE
RESPONSES ACROSS THE ENTIRE ORGANISM
One insight from multiomics data sets is the coordinated
molecular responses across multiple organ systems in re-
sponse to physical activity. These responses include spe-
cific pathways that are broadly activated across multiple
tissues, as well as the increased correlation of metabolic
profiles between anatomically segregated cell types and
organs. These studies collectively suggest that one effect
of physical activity is to reset and to coordinate molecular
processes across multiple organ systems.
For instance, several different multiomics data sets have
revealed a coordinated activation of the heat shock re-
sponse of multiple cell types and organs after exercise
training. Heat shock proteins (HSPs) are a family of an-
cient proteins that act as molecular chaperones, with the
specific role of preserving cellular homeostasis in response
to stress (10). Previously, Salo et al. (11) showed that a spe-
cific member of the HSP family, HSP72, is induced in spe-
cific tissues such as the liver and skeletal and cardiac
muscle after acute exercise. In combining transcriptomic
and proteomic analyses for 6-month-old rats of both sexes
after 8 weeks of treadmill training, the Molecular Trans-
ducers of Physical Activity Consortium (MoTrPAC) consor-
tium found evidence of a consistent activation of the heat
shock response across multiple organs—including the cor-
tex, heart, lung, liver, kidney, subcutaneous white adipose
tissue, and skeletal muscle (8). The degree to which the
Wei, Raun, and Long 163
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levels of heat shock proteins increased was notably influ-
enced by both the duration of exercise training and the sex
of the rats. For example, in male rats, an 8-week training
regimen resulted in a 16-fold increase in the abundance of
HSPA1B and HSPB1 proteins, whereas only a 2-fold in-
crease was observed after 1 week of training. Additionally,
the intensity of the exercise-induced heat shock response
was less significant in female rats, as the levels of individ-
ual HSPs did not increase by more than fourfold even after
an 8-week exercise training program (8).
Metabolomics data sets of exercise have also revealed
the rewiring of intertissue metabolic coordination by exer-
cise training (Fig. 2). Sato et al. (12) performed undirected
condition-specific correlation networks on >1,000 metab-
olites detected across eight tissues after a single bout
of treadmill running in 3-month-old male mice. They
showed that this exercise bout significantly increased the
correlation of metabolites across several organs, including
in the serum, liver, heart, hypothalamus, skeletal muscle,
brown adipose tissue, and epididymal and inguinal white
adipose tissue. Sato et al. further suggested that this in-
creased metabolite correlation between organs might re-
flect exercise-dependent shifts in fuel preference during
physical activity. For example, during exercise, an increase
in the correlation of amino acids was observed between the
heart-serum-liver, suggesting an increased amino acid fuel
coordination between these two organs. Similarly, exercise
increased the correlation between carbohydrates in brown
164 Multiomics Studies of Physical Activity Diabetes Volume 73, February 2024

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Figure 2—Highlighted discoveries related to physical activity enabled by multiomics technologies. Proteomics: using cell type–selective
plasma proteomics, Wei et al. (26) mapped the secretomes of 21 different cell types in mice after exercise training. Posttranslational modifica-
tions: exploring the phosphoproteomic landscape in skeletal muscle after three different exercise modalities, Blazev et al. (42) discovered a
novel AMPK substrate, C18ORF25. Metabolomics: Sato et al. (12) showed how the metabolomes of different tissues are altered after acute ex-
ercise. Li et al. (28) discovered a metabolite, Lac-Phe, that is induced by high-intensity exercise and is involved in appetite regulation. RNA se-
quencing: using RNA sequencing Sun et al. (13) showed that lifelong exercise training can maintain proper circadian rhythmicity of genes in
aging mice. Lipidomics: Stanford et al. (43) showed that acute exercise leads to the release of the lipokine 12,13-diHOME, which in turn alters
the whole-body metabolism. FC, fold change.

fat and lipids in inguinal white fat, suggesting that coordi-
nated carbohydrate/lipid metabolism serves as an axis for in-
teradipose cross talk in exercise. Another surprising finding
from the metabolite correlation network is that the hypo-
thalamus becomes the correlation hub between organs after
acute exercise. Some of the underlying correlation signals re-
vealed metabolites involved in amino acid metabolism, with
a strong enrichment of a class of poorly studied metabolites,
acetylated amino acids, after the exercise perturbation (30%
of the total correlated metabolites in amino acid metabolism)
compared with the sedentary condition (8%). For example,
an increase in correlation of N-acetyl-leucine was observed
between hypothalamus-serum-skeletal muscle, suggesting a
potential exercise-inducible metabolite shuttle between pe-
ripheral tissues and the brain.
Lastly, organism-wide multiomics has also revealed an
intimate and much more widespread connection between
exercise and circadian rhythms than previously recognized.
Recent studies have shown that exercise affects the transcrip-
tion levels of circadian clock genes across the body in an age-,
training regime–, and sex-independent manner but an exercise
training frequency–dependent manner. Using scRNA-seq, Sun
et al. (13) showed that a 12-month voluntary wheel running
intervention in 16-month-old male mice restored crucial cir-
cadian rhythm genes, such as transcription factor genes
Bmal1 and Dbp, to levels comparable with those seen in
2-month-old young mice (Fig. 2). This restoration occurred in
>30 of the 101 cell types identified in 14 major tissues. These
cell types include cells that reside in the central nervous sys-
tem, such as neurons, astrocytes, and oligodendrocytes, as
well as in the peripheral tissues, such as macrophages,
smooth muscle cells, and endothelial cells. Furthermore, these
exercise-inducible changes in circadian clock genes were also
observed in young mice. In another study involving 12-week-
old male mice exposed to 3 weeks of voluntary wheel running,
an enriched circadian rhythm pathway was identified in mes-
enchymal stem cells (MSCs) across skeletal muscle and subcu-
taneous and visceral white adipose tissue. After exercise, the
gene Dbp was once again increased, regardless of the diet
composition, in both chow- and high-fat diet–fed mice (14).
Using ATAC-Seq (assay for transposase-accessible chromatin
with sequencing) to map differentially accessible regions of
the whole genome, the MoTrPAC consortium showed that
open chromatin regions were enriched with sequence
diabetesjournals.org/diabetes
motifs recognized by key transcription factors in circadian
clock programs, namely BHLHE41, NPAS, and BMAL1.
This circadian clock gene change was sex independent, as
this regulation pattern was found in 6-month-old rats of
both sexes subjected to 8-week treadmill training (15). All
of these observations show that exercise resets central and
peripheral clocks in multiple tissues. Given that global and
tissue-specific disruptions of circadian rhythm programs
dramatically impair exercise adaptations and benefits (16),
these studies add to the growing body of evidence suggest-
ing complex and direct molecular interactions between
physical activity and circadian clocks across the organism.
MULTIOMICS OF CIRCULATING MOLECULES
THAT MEDIATE ORGAN CROSS TALK
A long-standing hypothesis is that exercise induces the
production of circulating signaling molecules, also known
as “exerkines” or “exercise factors,” that mediate tissue
cross talk and function as molecular effectors of physical
activity (17). The first evidence for such hormonal factors
dates back to 1961, when blood transfusions from exer-
cised dogs were found to lower blood glucose levels in rest-
ing dogs (18). For many years, research focused primarily
on secreted polypeptides from skeletal muscle, which have
also been referred to as “myokines.” However, recent mul-
tiomics studies have expanded both the cell types of origins
and the types of molecules that are induced by physical
activity.
A growing number of studies are indicating that
exercise-regulated bioactive plasma proteins originate from
multiple sources beyond muscle (19–26). For example, we
recently used a cell type–specific secretome tagging strategy
to identify new exercise-inducible secreted proteins (Fig. 2).
Our findings revealed that two intracellular carboxylester-
ases expressed in the liver generated extracellular proteo-
forms capable of antiobesity, antidiabetes, and endurance-
enhancing effects in mice (26). Additionally, in two distinct
studies with use of untargeted proteomic analysis of blood
plasma, the induction of a complement protein and a phos-
pholipase in mice subjected to voluntary wheel running was
reported. These proteins are primarily expressed in the liver
and were observed to reduce brain inflammation and en-
hance cognitive function, respectively (20,21). The findings
of these studies collectively suggest that the liver is an es-
sential contributor to the exerkine pools during exercise.
Besides the liver, other tissues such as bone can also act as
sources of exercise-induced bioactive plasma proteins. For
instance, after a single bout of treadmill running in mice
and humans, osteocalcin, a bone-derived circulating hor-
mone, was induced in circulation. Osteocalcin was found to
enhance glucose uptake and catabolism and increase fatty
acid oxidation in skeletal muscle. Notably, in mice, whole-
body loss of osteocalcin or skeletal muscle–specific deple-
tion of Gprc6a, the osteocalcin receptor, led to comparable
outcomes of impaired endurance capacity, as demonstrated
by a 20–30% reduction in running time and distance on a
Wei, Raun, and Long 165
treadmill (27). More examples of such non-muscle-derived
bioactive proteins can be found in a comprehensive review
by Chow et al. (17).
Beyond circulating polypeptides, physical activity also dra-
matically regulates the levels of circulating, bioactive metabo-
lites. Targeted and untargeted metabolomics analyses have
now identified hundreds of plasma metabolite changes fol-
lowing physical activity (12,17,22,28,29). For example, ma-
late and succinate, two metabolite intermediates in classical
glycolysis and TCA cycle pathways, are dramatically elevated
in blood plasma following exercise (22). These metabolites
can exert signaling functions, such as regulating muscle re-
modeling, cell cycle progression, brain function, and lipid oxi-
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dation (30–33). Additionally, untargeted metabolomics has
been a powerful approach for uncovering novel bioactive me-
tabolites associated with physical activity. For example, in
our recent study we identified a lactate–amino acid conjugate,
N-lactoyl-phenylalanine (Lac-Phe), to be robustly induced by
exercise across multiple species (28). Pharmacological
gain- and genetic loss-of-function studies demonstrate that
Lac-Phe regulates feeding and obesity. Exercise-inducible
Lac-Phe production is likely driven by the dramatically in-
creased circulating lactate during exercise and establishes an
unexpected role for lactate-derived metabolite in physical
activity (Fig. 2). Another example is the brown adipose–
derived linoleic acid metabolite 12,13-diHOME, which pro-
motes skeletal muscle fatty acid uptake (34). The increase in
circulating 12,13-diHOME immediately after a single bout
of exercise suggests that exercise-induced lipolysis may be
responsible for the elevated levels of this metabolite (Fig. 2).
These studies collectively suggest that key metabolite effec-
tors of exercise may be commonly derived from the principal
metabolic fuels (e.g., lactate or fatty acids) that are mobilized
during physical activity.
MULTIOMICS REVEALS RESPONSES OF
NONPARENCHYMAL CELLS TO EXERCISE
Traditionally, studies of the exercise response in key meta-
bolic tissues, such as adipose tissue, muscle, and liver, have
largely focused on molecular and physiologic changes at
the whole organ level. Recent advancements in multiomics
techniques, particularly in scRNA-seq, have enabled a high-
resolution reexamination of individual cell types’ response
in these major exercise-responsive tissues. This has led to
an increasing appreciation of nonparenchymal cell involve-
ment in the exercise response in adipose tissue and skeletal
muscle.
For example, it is well established that exercise training
induces muscle hypertrophy and increased capillary density.
However, there has not been a detailed understanding of
the cell types contributing to such remodeling. In analyzing
scRNA-seq data using pseudotime trajectory analysis in hu-
mans subjected to a single bout of cycling exercise, Lovri
c
et al. (35) demonstrated that the transcriptional features of
Pax71 satellite cells shifted toward Tnni21 fast-twitch and
Tnni11 slow-twitch myogenic cells. The authors concluded
166 Multiomics Studies of Physical Activity
that this satellite-to-myocyte transition explains the cellular
sources of increased density of muscle fiber after exercise.
This finding was further supported in another single-nuclei
sequencing study focusing on chronic exercise training.
Here, Wen et al. (36) showed that the number of Pax71/
Myf51 and Pax71/Myf5 significantly increased up to
50-fold after 4 weeks of weighted wheel training in mice.
They conclude that exercise training increases Pax71 satel-
lite self-renewal and maturation. Both of these studies un-
derscore the power of single-cell sequencing to define the
cellular basis and differentiation trajectories that underlie
skeletal muscle adaptations to exercise.
scRNA-seq has also revealed increased immune cell re-
cruitment and immune pathway activation in muscle and
adipose tissues following exercise. For example, in human
skeletal muscle, it was recently demonstrated that both the
lymphocyte cell population (including T, B, and natural killer
[NK] cells) and the monocyte cell population exhibited a sub-
stantial increase, from 4 to 9% and 2% to 4%, respectively,
following repeated bouts of all-out cycling sprints (35). In a
separate study of trained and untrained human subjects fol-
lowing acute bouts of bilateral knee extension, a Pathway-
Level Information ExtractoR (PLIER) deconvolution analysis
of microarray data showed an increased proportion of neu-
trophils, identified by marker genes such as S100A8 and
S100A9, in the skeletal muscle of both (37,38). Lastly, single-
cell transcriptomic analysis of white and brown adipose tis-
sues in male rats undergoing an 8-week treadmill training
regimen revealed a significant increase in the number of T,
B, and NK cells, as indicated by increased transcript abun-
dance of canonical immune cell markers and enriched im-
mune pathways such as the B and T cell receptor signaling
pathway, which was consistent with the findings in skeletal
muscle (8). The cellular origins of the increased immune cell
recruitment and activation in exercise, as well as the func-
tional consequences of perturbing this process for exercise
adaptations, remain unclear at this time.
MSCs in adipose tissue and muscle are another nonpar-
enchymal cell type that displays an unexpectedly strong re-
sponse to physical activity. These stromal cells have the
unique ability to self-renew and differentiate into various
cell types, depending on their location within the tissue.
Due to their low tissue abundance, e.g., <1% in adipose tis-
sue (39), MSCs have not been previously studied in the con-
text of exercise. A recent study with use of single-cell
transcriptomic analysis of skeletal muscle and subcutaneous
and visceral adipose tissues highlighted a central role of
MSCs in tissue adaptation to 3 weeks of voluntary running
in mice (14). Among 22 cell types identified within muscle
and fat, MSCs had the largest number of exercise-induced
differentially expressed genes. Pathway enrichment analysis
of these genes revealed the downregulation of extracellular
matrix remodeling, highlighting a previously unknown cellu-
lar contributor to local tissue remodeling. Similarly, in our
own work using a cell type–selective secretome profiling
approach (40,41), we showed that Pdgfra1 MSCs exhibited
Diabetes Volume 73, February 2024
the most robust secretome response across all of the cell
types studied in response to 1-week treadmill training in
mice (26). These cells could be found in adipose tissue and
muscle, as well as additional nonmetabolic tissues such as
the lung. Following exercise, Pdgfra1 MSCs released vari-
ous molecules into the bloodstream, including TIMP3,
which regulates extracellular remodeling; F13A, which is
involved in coagulation; and LOXL1, which contributes to
fibrosis. These findings suggest that MSCs play a systemic
regulatory role in the modulation of whole-body physiology
after exercise.
FUTURE PERSPECTIVES
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The use of multiomics approaches for analyzing molecular
changes during physical activity has revealed a more com-
plex exercise landscape than previously understood. This
comprehensive and unbiased strategy has unveiled sur-
prising results of exercise-induced effects, including the
dramatic exercise response of nonparenchymal cells, the
integrative response across tissues/organ systems, and
the intricate regulation of multiorigin exerkines. Despite
the wealth of data that has been collected, as well as the
new insights obtained, many open questions remain. Be-
low, we share our perspectives on four fertile and exciting
future research directions that are now addressable using
these high-dimensional tools.
THE COMPLEX ROLE OF LACTATE AND ITS
POTENTIAL AS A PRIMARY DRIVER OF THE
EXERCISE RESPONSE
Blood lactate levels are one of the most common blood meas-
urements during exercise testing, especially in athletes. By
both abundance and magnitude, lactate is one of the most dra-
matically regulated molecules in exercise: its levels can be ele-
vated >10-fold to >20 mmol/L after vigorous sprinting.
Beyond its primary metabolic role as an interorgan metabolic
fuel during exercise (e.g., the “lactate shuttle”), more recent
studies have identified even more unexpected functions for
lactate in the context of the response to physical activity. For
instance, we recently showed that the role of lactate also
extends to lactate-derived metabolites such as Lac-Phe, an
exercise-inducible signaling metabolite that suppresses food
intake and obesity (28). In addition, extracellular lactate can
directly induce the secretion of intracellular carboxylesterase
proteins from hepatocytes, which function as bioactive circu-
lating plasma proteins that regulate energy metabolism (26).
That some of these roles have only been identified, or further
expanded upon, in the past few years suggests that we are
only in the early stages of understanding the diversity of lac-
tate functions in exercise physiology. One possibility for
speculation is that lactate elevation functions as a key driver
for numerous secondary downstream molecular events in
exercise. Such a hypothesis has not been rigorously tested
but may provide a unifying framework for understanding
and organizing the thousands of molecular changes that
occur in response to physical activity. We propose future
diabetesjournals.org/diabetes
studies should prioritize exploring other potential roles of
lactate in exercise biology, as well as a consideration of how
lactate might function as a coordinating signal between the
molecular responses to physical activity.
BIDIRECTIONAL AND CELL TYPE–SPECIFIC
RESPONSES TO EXERCISE
Despite specific exercise responses being conserved across
many cell types—such as upregulated heat shock response
and changes in circadian clock programs—many other cel-
lular responses are tissue and cell type specific and can be
opposite depending on the tissue/cell type. For example,
exercise training leads to the recruitment and activation
of immune cells in both white adipose tissue and skeletal
muscle, while decreasing the number of immune cells in
the small intestine of rats (8). This contrast in regulation
patterns between these different tissues indicates that
the immune effects of exercise are specific to each tissue.
Additionally, our recent studies profiling secreted proteins
released by different cell types revealed bidirectional regu-
lation of the same proteins in different cell types by exer-
cise. For example, secretion of a superoxide dismutase
was suppressed from pancreatic b-cells but induced from
myocytes and Pdgfra1 MSCs in mice following 1 week of
treadmill training (26). Taken together, these studies
show that many cellular responses to exercise are depen-
dent on the specific cell types under study and include
many cell types that have not classically been studied as
part of the exercise response. Therefore, higher-resolution
approaches that can be applied in a cell type–specific or
organ-specific manner become increasingly important for
understanding these bidirectional responses to physical
activity, which may become masked in studying more
“bulk” samples. Importantly, future studies in this area
should also be focused on capturing unusual cell types for
an understanding of the diversity of cellular responses to
exercise beyond those of classical metabolic tissues.
A GROWING NEED FOR LOSS-OF-FUNCTION
STUDIES OF EXERKINES
The majority of studies on candidate, exercise-inducible cir-
culating molecular effectors have relied heavily on gain-
of-function experiments. There are limited data available
from loss-of-function models. Consequently, whether candi-
date molecules are truly necessary for a particular physio-
logic effect of physical activity has remained a largely
unanswered question. The lack of loss-of-function studies is
due, in part, to technical challenges. For instance, interpreta-
tion of genetic manipulation of secreted proteins can be
complicated due to concurrent ablation of intracellular
pools, which may have additional or secondary functions.
Neutralizing antibodies are typically not readily available for
most circulating polypeptides. For exercise-inducible metab-
olites, robust methods for their genetic manipulation can be
difficult due to multiple biosynthetic pathways and/or unde-
fined molecular pathways for their efflux from cells. The
Wei, Raun, and Long 167
development of new tools in this area, such as neutralizing
nanobodies or engineered enzymes for manipulation of spe-
cific metabolite pathways, may enable the key functional ex-
periments that demonstrate physiologic roles for exercise-
inducible circulating effectors in metabolism and physiology.
“EXERCISE AS MEDICINE”—AN UNREALIZED
DREAM
A crucial and exciting future direction of exercise research
involves developing “exercise mimetics” that can pharmaco-
logically imitate a wide range of health benefits associated
with physical activity. Most past efforts toward such mole-
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cules have primarily targeted pathways that improve exer-
cise performance. For example, erythropoietin increases
hematocrit and VO2max for endurance performance; simi-
larly, testosterone and other androgen receptor agonists in-
crease lean mass and strength. However, performance is not
health. Salutary effects such as reduced cardiovascular mor-
tality, increased bone strength, and improved brain health
have yet to be conferred by therapeutic capture of exercise-
regulated molecules or pathways. As multiomics techniques
advance and we acquire more knowledge about the non-
muscle/nonperformance benefits, we may discover new
molecules and opportunities to truly translate the concept
of “exercise as medicine” into reality.
SUMMARY
Exercise induces profound molecular changes on an organism-
wide scale. In previous studies investigators have focused on
characterizing individual exercise-regulated molecules and
specific organs such as muscle and fat. Recent technical ad-
vances in multiomics technologies have allowed for deep
mapping of molecular changes across the entire organism
and at high resolution. These data sets have revealed thou-
sands of molecular changes that are dependent on the exer-
cise subject (such as species, age, and sex), exercise modality
(acute vs. chronic, voluntary vs. involuntary, intensity and
frequency), and a variety of environmental factors (such
timing of exercise). They have also provided important in-
sights into exercise physiology that were previously not well
understood, such as the role of exercise to coordinate molec-
ular processes across multiple organ systems, or the dynamic
responses of nonparenchymal cells to physical activity. We
anticipate that in providing high-resolution insights into
physical activity, these multiomics technologies will provide
new insights that serve as a foundation for therapeutic
“capture” of the benefits of physical activity for human
health.
Acknowledgments. The authors thank members of the J.Z.L. and
K.J. Svensson (Stanford University) laboratories for helpful discussions. The
authors apologize for not citing the many other excellent articles in this area
due to space limitations.
Funding. This work was supported by the National Institutes of Health
(DK105203 and DK124265) and the Wu Tsai Human Performance Alliance.
168 Multiomics Studies of Physical Activity
Duality of Interest. No potential conflicts of interest relevant to this arti-
cle were reported.
Prior Presentation. Parts of this study were presented in abstract form
at the 83rd Scientific Sessions of the American Diabetes Association, San Diego,
CA, 23–26 June 2023.
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