TEM 1717 No.

of Pages 11

Trends in
Endocrinology & Metabolism
Review

Contributions of physical inactivity and

sedentary behavior to metabolic and
endocrine diseases
Nathan R. Kerr1 and Frank W. Booth 1,2,3,4,
*

Physical inactivity is the fourth leading global cause of death and is a major con- Highlights
tributor to metabolic and endocrine diseases. In this review we provide a current Physical inactivity and sedentary behavior
update of the past 5 years in the field as it pertains to the most prevalent and are major contributors to endocrine and
metabolic diseases.
deadly chronic diseases. Despite the prevalence of physical inactivity in modern
society, it remains largely overlooked relative to other comparable risk factors Recent clinical studies show bed
such as obesity, and our molecular understanding of how physical inactivity rest induces insulin resistance, reduced
impacts metabolism is still partially unknown. Therefore, we discuss current VO2max, increased blood pressure, etc.

clinical inactivity models along with their most recent findings regarding health
People that are classified as physically
outcomes along with any discrepancies that are present in the field. Lastly, we inactive are 1.4 times more likely to de-
discuss future directions and the need for translatable animal models of physical velop dementia, and insulin resistance is
inactivity to discover novel molecular targets for the prevention of chronic disease. hypothesized to drive cognitive decline.

The most physically inactive individuals

are 1.75 times more likely to develop
cardiovascular disease, as inactivity is
Why study physical inactivity? one of the greatest single risk factors.
Physical inactivity, defined by not reaching the recommended levels of weekly physical activity
Aging and declining physical activity
(at least 150 min of moderate-intensity aerobic activity per week), is now recognized as the fourth
levels lead to sarcopenia and muscle
leading cause of death and has been demonstrated to be a contributor to 40 chronic diseases atrophy, which is associated with an
[1–3]. Conservative estimates from 2016 place the worldwide economic burden due to physical increased risk of premature death.
inactivity to be between US$53.8 and $67.5 billion [4]. Regarding prevalence, the Centers for Dis-
ease Control (CDC) estimates that 25.3% of US adults do not meet the guidelines for physical ac-
tivity. However, these numbers were collected through telephone interview surveys where
participants were simply asked if they did any physical activity outside of their regular job, and if
the answer was yes, they were considered physically active [5]. This is likely a gross underestimation,
and more objective measurements through the use of pedometers or accelerometers are required
1
for a true estimation of the levels of inactivity [6]. Not only is physical inactivity highly prevalent, but Department of Biomedical Sciences,
University of Missouri, Columbia, MO
sedentary behavior, which can be defined independently of physical inactivity as large durations of
65211, USA
time spent sitting, reclining, or lying down continues to increase as well [7]. To clarify, a major distinc- 2
Department of Nutrition and Exercise
tion between physical inactivity and sedentary behavior is that a person can meet the guidelines of Physiology, University of Missouri,
Columbia, MO 65211, USA
physical activity yet still engage in excessive amounts of sedentary behavior leading to increased 3
Department of Medical Pharmacology
disease risk, making sedentary behavior its own independent risk factor. and Physiology, University of Missouri,
Columbia, MO 65211, USA
4
Dalton Cardiovascular Research Center,
Among these 40 chronic diseases associated with physical inactivity, we will focus on those
University of Missouri, Columbia, MO
spawning from metabolic and endocrine dysregulation with the purpose of encouraging 65211, USA
researchers to study these diseases from the perspective of inactivity, as our molecular under-
standing in this area is currently still lacking. More importantly, inactivity levels are likely reaching
an all-time high due to the recent coronavirus disease 2019 (COVID-19) pandemic (Box 1). We
hope to underscore the importance of studying the role physical inactivity plays in the development *Correspondence:
and pathophysiology of the most prevalent metabolic- and endocrine-related diseases (Figure 1). BoothF@missouri.edu (F.W. Booth).

Trends in Endocrinology & Metabolism, Month 2022, Vol. xx, No. xx https://doi.org/10.1016/j.tem.2022.09.002 1
© 2022 Elsevier Ltd. All rights reserved.
 Trends in Endocrinology & Metabolism

Box 1. Impact of COVID-19 on inactivity and related diseases

Recent studies have used the COVID-19 pandemic in order to predict how the increased physical inactivity due to lock-
downs may have major consequences on the prevalence of chronic diseases. During lockdowns, people of all ages were
unable to meet their activity goals during the pandemic, as fitness centers, gyms, and physical education through in-
person schooling was put on hold for the duration [66]. In fact, a study by Tison et al. showed that 30 days into the
pandemic, mean daily step counts had decreased by a staggering 27.3% [67,68]. One group analyzed the impact of
COVID-19-induced physical inactivity on CVD and came up with these estimates. Eliminating physical inactivity in patients
with coronary heart disease would prevent 399 000 coronary heart disease deaths, while a 25% increase in physical
inactivity levels, potentially as a consequence of the pandemic, could lead to ~105 000 additional coronary heart disease
deaths in the coming years [69]. Another study found that type 2 diabetics showed a significant increase in time spent
sedentary and a decrease in engagement in physical activity during the pandemic, ultimately leading to a negative meta-
bolic impact and likely significant repercussions in the near future [70].

Physical inactivity/sedentary behavior is molecularly distinct from exercise

Historically, physical activity has received significantly more funding relative to physical
inactivity and sedentary behavior. For example, according to the National Institutes of Health
(NIH) RePORT, the number of funded NIH grants in 2010 and 2021 with ‘physical activity’ in
the title were 2272 and 2815, respectively, whereas the number of funded NIH grants with
the words ‘sedentary behavior’ in the title in those same years were 208 and 286, which
equates to only one tenth of the amount of funding that physical activity received. We believe
this lack of attention has led to a highly relevant field that remains understudied relative to
comparable risk factors such as obesity and smoking. Fortunately, there has been a gradual
and steady increase in the number of studies focusing on the effects of inactivity and seden-
tary behavior – rather than only on physical activity/exercise – on a disease state. The tide
began to shift in 2011 when Thorp et al. [8] performed a systematic review of papers

Consequences of Physical Inactivity and Sedentary Behavior

Risk of Dementia Risk of Cardiovascular Disease

VO2 max
Amyloid beta levels Atherosclerosis
Shear-rate & peripheral blood
Brain insulin resistance Blood pressure
flow
Microvascular function

Muscle VO2
Insulin sensitivity
Glucose uptake
Risk of type II Diabetes Risk of sarcopenia & metabolism
Hepatic insulin resistance H2O2 emissions Mitochondrial efficiency
Triglyceride accumulation Neuromuscular junction damage

Trends in Endocrinology & Metabolism

Figure 1. Major systemic consequences of chronic physical inactivity and sedentary behavior. VO2max: maximal
oxygen consumption. Graphic created in house by departmental multimedia specialist, Donald Connor. The graphic was then
imported into Biorender where the rest of the figure was completed by the authors.

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spanning 1996–2011 supporting that sedentary behavior is a distinct risk factor that should
be viewed independently of physical activity, and provided evidence by exclusively analyzing
sitting time and its relation to mortality and disease incidence. Most of the studies they an-
alyzed demonstrated that sedentary behavior was a significant risk factor that was indepen-
dent of physical activity levels [8]. Since these initial findings, a molecular understanding of
the consequences of physical inactivity and sedentary behavior still continue to be lacking,
in our opinion, as we search for proper experimental designs that allow us to accurately
study inactivity independent of physical activity. One experimental design that has com-
monly been used to study inactivity/sedentary behavior under extreme circumstances is
the bed-rest model [9,10].

First used as a model to simulate deconditioning in space flight and zero gravity, bed rest is still
commonly used as a model for studying the consequences of physical inactivity today [11].
More recently, meta-analyses have been performed to analyze the relationship between bed
rest and maximal oxygen uptake (VO2max) [12]; they found a highly significant inverse correlation
between bed-rest duration and VO2max (R2 = 0.35, P < 0.001), indicating that as sedentary levels
progressively increase, VO2max decreases stepwise. They also went on to show that individuals
with a higher VO2max appear to be more susceptible to a decrease in VO2max following bed
rest, highlighting the importance of consistently maintaining activity levels throughout life in
order to fully reap the benefits of physical activity. These findings are highly important, as
VO2max has been demonstrated to be a strong predictor of all-cause mortality [13]. Another inter-
esting bed-rest study from 2017 had healthy lean men undergo 8 days of bed rest, and evaluated
numerous outcomes such as insulin resistance, body composition, and imaging of the brain and
abdomen. Following the 8 days of bed rest, researchers found a 12% drop in VO2max, induction of
insulin resistance, increased visceral fat, and elevated plasma cortisol and tumor necrosis factor α
(TNF-α). It is worth mentioning that this study incorporated a group that underwent alternate-day
caloric restriction to potentially blunt the detrimental effects of bed rest. However, this had little to
no beneficial effect on the measured outcomes and produced greater insulin resistance [14].
We emphasize this point because fasting has been suggested to work through mechanisms sim-
ilar to those of physical activity; therefore, these findings indirectly provide evidence that the ef-
fects of inactivity/sedentary behavior are unique compared to the mechanisms of physical
activity [15–17].

Building on these findings, a 2020 bed-rest study by Fernandez-Gonzalo et al. analyzed

changes in the skeletal muscle transcriptome of males, with one group undergoing 84 days
of bed rest and the second group undergoing a flywheel resistance exercise (RE) program in
addition to the bed rest. While RE was able to counteract most bed-rest-induced tran-
scriptome changes, they found that there were still 209 sedentary-related transcripts that
were resistant to the exercise treatment [18]. Overall, this study and many others have
shown that exercise is capable of restoring most functional deficits caused by inactivity [19];
however, this study provided evidence that certain inactivity-related molecular changes are in-
dependent of exercise and persist in the presence of exercise. It is worth mentioning this effect
could be due to the exercise modality used in the study, and it is possible that an aerobic ex-
ercise intervention would have a greater effect on the transcriptome than RE. These findings fur-
ther support the idea that physical inactivity and sedentary behavior likely have their own unique
molecular mechanisms, highlighting the importance of reducing time spent being inactive or sed-
entary even in individuals who performed planned exercise on a regular basis [18]. In fact, the
World Health Organization’s (WHO’s) 2020 guidelines recommended reducing sedentary time;
however, they did not provide an exact guideline on duration, likely because of the need for
more data on the topic [20,21].

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Recent findings on the role of physical inactivity and sedentary behavior in major
diseases
Physical inactivity is a major contributor to insulin resistance and type II diabetes
In 2004, a landmark paper established physical inactivity as an independent risk factor for the
development of type 2 diabetes mellitus. This laid the foundation for current research to shift
focus toward the contributions of inactivity and sedentary behavior to insulin resistance and
type 2 diabetes [22]. Recently, a study by Dirks et al. had 20 healthy 25-year-old males undergo
1 week of bed rest, and found a significant reduction in insulin sensitivity which was associated
with reductions in glycogen synthase, hexokinase, and AS160 protein levels taken from a muscle
biopsy of the medial vastus lateralis, indicating a decrease in glucose uptake and metabolism
[23,24]. They also showed reductions in skeletal muscle state III respiration, maximal oxidative
phosphorylation, and ADP sensitivity. A significant increase in H2O2 production was present,
but this did not correlate with insulin resistance severity, indicating that mitochondrial H2O2 emis-
sions did not explain how bed rest induces insulin resistance [25]. However, it is worth mentioning
that a similar study with 10 days of bed rest did not see changes in citrate synthase activity, ADP
sensitivity, or maximal oxidative phosphorylation. However, the study did find that transitory limb
ischemia following 10 days’ bed rest showed a 25% reduction in resting muscle VO2 [26]. There
are numerous recent examples of discrepancies in experimental findings, such as the two studies
just described, which could be explained by the use of within-subject pre-bed-rest measure-
ments serving as controls rather than including an age-matched control group [25,27,28]. Future
studies may benefit from taking this experimental design into consideration in order to further
elucidate mechanisms by which physical inactivity alters mitochondrial respiration and insulin
sensitivity, and whether those two factors are causally linked.

As in the bed-rest experiments described, daily step-count reduction has also been used to
study the relationship between physical inactivity and metabolism. A study from 2018 had
young adult participants (~36-year-old males and females) undergo 14 days of step reduction
[29] and showed that not only did VO2max decline, but there were significant metabolic conse-
quences such as peripheral insulin resistance, leading to liver triglyceride accumulation and
subsequent hepatic insulin resistance. It was also shown that in the 14 days of reduced daily
steps, increases in blood pressure accompanied the liver changes mentioned earlier, poten-
tially also contributing to increased cardiovascular disease (CVD) risk. Fortunately, after the
14 days of step reduction ended, participants had these parameters remeasured after returning
to 14 days of normal activity, and the health parameters of all of the young and healthy participants
had returned to normal levels. However, another study done around the same time conducted a sim-
ilar test in overweight older adults (~70 years old) and, similarly, they saw impairments in glycemic
control and muscle protein synthesis after 14 days of step reduction. But, unlike the young and
healthy cohort, their health parameters did not return to baseline levels after 14 days of recovery
[30], demonstrating that the elderly were not able to recover from bouts of inactivity as did the younger
individuals. In summary, the relationship between physical inactivity and insulin resistance is an impor-
tant metabolic initiator to many prevalent chronic diseases [31] that we will discuss in the rest of this
review. Unfortunately, the number of recent clinical studies that have investigated this relationship is
limited, and our molecular understanding of how physical inactivity induces insulin resistance has
yet to be elucidated.

The first major chronic disease that comes to mind when one thinks of insulin resistance is, of
course, type 2 diabetes mellitus. One recent study investigated the effect of varying levels of inactivity
across three groups of type 2 diabetics who (i) sit 14 hours per day and take 4415 steps per day
(sit group), (ii) take 4823 steps with 14 h of sitting, except one of these sitting hours consisted of
moderate to vigorous cycling each day (exercise group), or (iii) only 4.7 h of sitting per day frequently

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interspersed with light walking to achieve 17 502 steps per day for a total of 4 days (sit-less group).
They found that the exercise group did not receive any benefits over the sit group, indicating that the
high levels of inactivity/sedentary behavior outweighed the benefits of their 1.1-h exercise regimen.
On the other hand, the sit-less group showed a reduction in blood glucose levels, insulin resistance,
and time spent in hyperglycemia throughout the day, demonstrating that decreasing the time spent
being physically inactive and sedentary was most effective and had the greatest metabolic benefit
[32]. Current and updated estimates for the contribution of inactivity to diabetes are lacking, but
one of the last noted estimates from 2008 attributed 6–10% of all type II diabetes cases to physical
inactivity [33], making research geared towards studying how physical inactivity drives this metabolic
disease highly relevant.

The endocrine connection between physical inactivity and dementia

The link between inactivity and insulin resistance goes beyond type II diabetes, as recent data sup-
ports a connection between insulin resistance and cognitive decline, leading to a term coining the
link between type II diabetes and Alzheimer’s disease as ‘type III diabetes’ [34]. A meta-analysis
performed in 2019 examined whether physical inactivity was a risk factor for the development of
dementia; this study found that physical inactivity was associated with an increased risk of coronary
heart disease, stroke, and most importantly, diabetes [35]. Many new studies are demonstrating
that endocrine abnormalities such as insulin resistance drive the pathology of Alzheimer’s disease.
For instance, Delikkaya et al. used a rat model for Alzheimer’s to demonstrate that impaired insulin
signaling perturbed the clearance of amyloid β as well as amyloid precursor protein (APP) process-
ing [36]. Around the same time a similar study was conducted that used an insulin-resistant
Alzheimer’s disease mouse model to show that the brain directly undergoes insulin resistance,
and that there is less insulin present in the cerebrospinal fluid in Alzheimer’s disease. They also
showed that inducing insulin resistance eventually led to an increase in amyloid β production,
which would infer that insulin resistance precedes amyloid β accumulation and could be one of
the initiating causes. Not only that, but after inducing insulin resistance and increasing amyloid β,
they could partially reverse the effects through caloric restriction, further implicating insulin resis-
tance as a contributor to Alzheimer’s disease [37]. Findings like these have led to the
hypothesis that insulin resistance in the brain increases amyloid β production while also decreasing
the metabolic capabilities of astrocytes and neurons, as they primarily rely on glucose metabolism,
leading to the hallmark signs of pathology such as plaque formation, atrophy of the hippocampus,
and deficits in cognition. Currently, one of the best treatments for combating insulin resistance is
physical activity [38], making studies geared toward determining the molecular mechanisms of
exercise and of physical inactivity on insulin signaling of paramount importance in the fight against
dementia [34].

Referring back to the meta-analysis mentioned at the beginning of this section, the study went on
to show that subjects (404 840 participants, mean age 45.5 years) who were classified as physi-
cally inactive had a hazard ratio of 1.4 for developing dementia within the next 10 years, meaning
they were 1.4 times more likely to get dementia than their regularly physically active counterparts.
Potentially even more important is that subjects who were classified as physically inactive and had a
cardiometabolic disease, such as diabetes or coronary heart disease, were at an even greater risk
of developing dementia compared to those with cardiometabolic disease alone, emphasizing the
importance of increasing physical activity levels even when facing chronic disease [35]. In support
of this, another recent meta-analysis from 2020 demonstrated that those who were physically
active as older adults were at a reduced risk of developing Alzheimer’s disease or dementia and,
most importantly, they had a reduced risk of all-cause mortality [39]. Thus, studies investigating
the relationship between inactivity and brain insulin resistance are needed as they could provide
novel therapeutic targets in the fight against cognitive decline.

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Physical inactivity and CVD

Next, we will discuss what is likely the most important risk factor associated with physical inactivity:
CVD. CVD has been the leading cause of death worldwide and in the US for the past century [40].
Physical inactivity is one of the greatest single factors contributing to CVD [3,41]. A study from 2018
analyzed associations between sitting time and CVD prevalence and found that sitting time was
associated with risk of CVD and all-cause mortality. Not only that, but they also found that the
strongest association between sitting and CVD was when sitting times approached >6 h per day
[42]. A separate study incorporated both physical activity levels and time spent sitting to determine
the joint association they have with CVD mortality, and they were able to demonstrate that the
highest risk (hazard ratio ~1.75) was found in individuals who had both the lowest amount of
physical activity and the highest levels of time spent sedentary. Interestingly, those with the lowest
amount of physical activity time but less than 4 h per day of time spent sedentary had a much lower
hazard ratio (~1.35), supporting that even physically inactive individuals have a lot to gain by
decreasing their time spent sedentary. Additionally, time spent sedentary had less of an impact on
CVD mortality as their physical activity levels increased, showing that very high levels of physical ac-
tivity can overcome large durations of sedentary behavior [43,44]. In support of this, a recent paper
studied what is referred to as the ‘weekend warrior’ strategy in which people acquire the bulk of
their physical activity in one or two sessions per week, rather than spreading their physical activity
across multiple days of the week. The ‘weekend warrior’ likely represents a population that meets
weekly physical activity requirements yet has higher levels of time spent sedentary relative to regularly
active individuals. The weekend warriors did have similar all-cause mortality levels to the regularly
active group, but unlike the regularly active group, the weekend warriors did not have significantly
lower all-cause mortality levels relative to the inactive group. This suggests that the weekend warrior
strategy is still partially beneficial, but not to the same extent as regular activity, which could be
explained by increased levels of time spent sedentary in the weekend warriors [45].

A handful of step-reduction and long-term sitting studies has been done since 2016 that
have analyzed changes in the vasculature in response to inactivity. The first of these studies
analyzed the relationship between prolonged sitting and leg endothelial function in healthy
young men. They found that in just 3 h of sitting, the shear rate in the popliteal artery was
reduced, indicating a decrease in blood flow. This reduction in shear stress was rescued
by heating one of the legs in order to restore blood flow. This work demonstrated that pro-
longed sitting reduces blood flow to the legs and could play a role in atherosclerosis in the
periphery [46]. Shortly after this a follow-up study demonstrated that intermittent fidgeting
could prevent the endothelial dysfunction and reduced blood flow brought on by prolonged
sitting by significantly increasing blood flow, shear-rate, and flow-mediated dilation of the
popliteal artery relative to the control leg [47]. Five days of step reduction rather than limb
immobilization was able to replicate their previous findings, implicating physical inactivity along
with sedentary behavior in decreasing peripheral blood flow to the legs [48]. More recently, it was
demonstrated in healthy young men that shear rate and microvascular function are significantly re-
duced after only 10 min of sitting, while macrovascular function is unaffected. Even more interesting
is that a recovery period of 1 h was unable to fully recover the decrease in shear rate and reactive hy-
peremia. They went on to repeat the experiment with participants lying down, and found that this also
reduced microvascular function, but the drop could be prevented by contracting the calf muscles
while supine [49]. While these short-term changes in function are proadaptive physiological
responses, under chronic conditions, these disuse-induced changes turn pathological, and future
research in this area is needed as we do not fully understand when or how this occurs. This demon-
strates that the microvasculature may be very susceptible to inactivity induced changes, which likely
leads to pathological effects, and that even a small amount of physical activity (i.e., calf muscle con-
tractions) can prevent these detriments.

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While there is an abundance of data supporting the connection between CVD, all-cause mortality,
and physical inactivity, we would like to highlight the importance of studying sex differences, an
area in the field that remains understudied due to a lack of female inclusion in much of the work
discussed thus far. Therefore, we will briefly mention some recent work emphasizing the sex-
dependent effects of exercise on older adults – specifically in regard to postmenopausal women,
who obtain less cardiovascular benefit from exercise – and encourage future research in this
area. These studies have shown that when postmenopausal women were supplemented with
estrogen, they were able to receive the vascular benefits from exercise, but without estrogen
these benefits were lost. The findings above emphasize that a differential response to exercise is
present between sexes, thus making extrapolation of data from male-only studies to females likely
inaccurate and oversimplified. Therefore, we hope to highlight and encourage future studies focus-
ing on the importance of studying females and female sex hormones in exercise, physical inactivity,
and cardiovascular health [50].

Physical inactivity and sedentary behavior induce sarcopenia and muscle atrophy with aging
Another disease worth discussing due to its high prevalence is sarcopenia, which occurs at rates
ranging from 11% to 50% in the 80+ years age group [51]. Aging has been shown to be coupled
with a decline in physical activity levels, ultimately leading to increased instances of sarcopenia
and frailty [52]. Older adults who are classified as frail have an increased risk of falling which
can lead to major disabilities, hospitalizations, and premature death [53]. In 2017, Phillips et al.
shed light on the presence of a negative correlation between age and muscle growth. The
study had young, middle-aged, and older men and women undergo a 20-week resistance exer-
cise training program to evaluate the effects of resistance training across various ages. Only the
young participants saw an increase in whole body lean mass and skeletal mass index, with
both of these outcomes showing a negative correlation with age. However, all age groups saw
similar improvements in whole-body strength, muscle quality, and insulin sensitivity [54]. These
data demonstrated that resistance training helps prevent sarcopenia with aging, but that older
and even middle-aged individuals have greater difficulty in achieving skeletal muscle hypertrophy
and preventing sarcopenia. Another study by Phillips et al. in 2020 focused on characterizing the
effects of muscle loading and unloading on the transcriptome. They took a unique approach to
studying the molecular effects of loading and unloading by using a within-subject design, having
one leg on a given subject undergo a loading protocol while the contralateral leg underwent the
unloading protocol. This strategy attempts to reduce heterogeneity between individuals, likely
resulting in a more accurate and sensitive measurement of muscle protein synthesis regulators.
As expected, muscle protein synthesis increased by ~13% in the loaded limb after 10 weeks,
while the unloaded limb saw a near 10% decrease after only 2 weeks, demonstrating that muscle
atrophy occurs about five times faster than muscle growth. Many of the differentially regulated
gene networks in their study were centered around mitochondrial function and angiogenesis,
which both play a key role in vascularization during muscle growth. The molecule FKBP1A was
linked to protein synthesis and was shown to interact with genes KLF9, NFIA, and RBPJ which
play a key role in angiogenesis. Another important mediator found in this study was BCAT2,
which was positively correlated with gains in lean mass, and when knocked down in cultured
primary muscle cells resulted in reductions in protein synthesis and downregulation of genes
involved in muscle growth [55].

A study from 2021 used limb immobilization to evaluate changes in forearm glucose uptake due to
the loss of muscle contraction, and found that after 48 h of arm immobilization, forearm glucose
uptake was reduced by 57% even though brachial arterial blood flow remained unchanged. This
provides another example of the need to understand on a molecular level what drives the transfor-
mation of an acute proadaptive response into a pathological one under chronic conditions of

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inactivity [56]. Salvadego et al. had healthy males (~27 years old) undergo 21 days of bed rest and Outstanding questions
saw a significant reduction in lean thigh mass, VO2peak, and maximal ADP-stimulated mitochondrial What inactivity-induced molecular
respiration and increased mitochondrial leak [27]. This would indicate that bed rest produces changes are independent from exer-
cise in various affected tissues?
muscle atrophy potentially due to a loss of mitochondrial efficiency. A similar study had 20
women undergo single leg immobilization for 2 weeks, with one group receiving omega-3 fatty How does exercise partially or
acid supplementation. They also found reductions in ADP-stimulated maximal mitochondrial completely mitigate inactivity-induced
respiration after 3 days of leg immobilization. Molecular analysis revealed changes in the MFN-2 metabolic and endocrine disorders?
to DRP-1 ratio, two proteins that regulate mitochondrial fusion and fission, respectively. There What is the molecular mechanism for
was a significant reduction in the control-leg immobilization group, indicating higher amounts physical inactivity-induced insulin re-
of mitochondrial fission; this effect was prevented with omega-3 fatty acid supplementation. sistance, and how are the mechanisms
Even more impressively, omega-3 supplementation prevented reductions in ADP-stimulated connected to cognitive decline, muscle
atrophy, etc.?
respiration; this was associated with the rescuing of adenine nucleotide translocator (ANT)
protein expression, an ADP/ATP translocase that exchanges ATP with ADP across the inner How do bed-rest (sedentary behavior)
mitochondrial membrane, demonstrating that maintaining ANT expression could prevent and step-reduction (physical inactivity)
study findings compare or differ? Do
detriments in mitochondrial bioenergetics during leg immobilization [57]. Another study from
these two types of inactivity have
2020 investigated the relationship between sarcopenia and physical inactivity in contributing unique mechanisms?
to deaths in people with nonalcoholic fatty liver disease (NAFLD). They found that there was
a strong inverse correlation between physical activity levels and sarcopenia in both people How has COVID-19 impacted the
prevalence of physical inactivity, and
with and without NAFLD. Most importantly, they found that physical inactivity was associated what will be the downstream impacts
with sarcopenia, and that sarcopenia was subsequently associated with an increase in mortality in on the occurrence of chronic diseases?
NAFLD patients [58].
When do proadaptive physiological
responses to physical inactivity turn
In 2020, two studies showed that physical inactivity leads to muscle atrophy, neuromuscular pathological, and what are the
junction damage, and even muscle denervation, demonstrating that inactivity also produces molecular mechanisms responsible
damage to the peripheral nervous system that innervates skeletal muscle [59,60]. The study for this switch?
done by Kilroe et al. showed that atrophy of the quadriceps occurred after only 2 days of leg
immobilization, and that muscle atrophy occurs at an exponential rate when a state of complete
inactivity is maintained [59]. However, despite these advancements in recent findings, our molecular
understanding of how inactivity drives sarcopenia and muscle atrophy requires further investigation,
as there is currently no drug that prevents sarcopenia.

Concluding remarks and future perspectives

Despite the major research setbacks that the COVID-19 pandemic has produced, this review
emphasizes the continued progress and advancements in our molecular understanding of the
effects of physical inactivity on metabolic and endocrine functions. However, more work is
needed to clear up the large number of discrepancies in the field and to discover more targets
that can potentially provide novel therapeutic targets for some of the world’s most prevalent
diseases (see Outstanding questions). In all of the disease states discussed in this review,
physical inactivity has been shown to be an initiating event [3]; therefore, we would propose
that gaining an understanding of the molecular consequences of physical inactivity will provide
us with targets that prevent chronic disease occurrence, rather than attempting to treat it. As
mentioned earlier, the CDC estimates on physical inactivity are likely underreported, as studies
have shown that men overestimate their physical activity levels by 44% while women overesti-
mate their physical activity levels by a staggering 138%, so it is safe to say that physical inactivity
levels are far more prevalent than currently estimated [6,40]. It is also worth pointing out that the
prevalence of the major diseases discussed herein are either being maintained or increasing
[61–63]; thus, one could contend that there is likely a strong correlation between the prevalence
of chronic disease and inactivity. Furthermore, physical inactivity is a particularly unique risk factor
in that it contributes to/causes the prevalence of other top risk factors such as obesity,
depression and anxiety, high blood pressure, and poor diet [41].

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We propose that future studies should incorporate the use of translational animal models ac-
companied by clinical studies (i.e., a bench-to-bedside approach) in order to combine physio-
logical outcomes in humans with more invasive molecular experiments in animals, especially in
regard to inaccessible or highly invasive human tissues such as the brain, liver, pancreas, etc.,
tissues which are difficult or impossible to study at the molecular level without using animal
models. Currently, animal models of physical inactivity are limited. Of the few that there are,
tail limb suspension and limb casting rodent models allow for the study of inactivity on skeletal
muscle and insulin resistance and could provide a more in-depth molecular understanding of
the processes of metabolic dysregulation and sarcopenia. However, one must be careful
with direct extrapolation of animal studies to humans. Animal studies are most translatable
when done in conjunction with human studies, and the use of correlational analysis between
the two is an important way to estimate the translatability of findings. Therefore, we highlight
the necessity of collaboration between clinical and basic research laboratories in order to
fully elucidate the molecular mechanisms involved. Regarding additional animal models of inac-
tivity, our laboratory has generated selective breeding models of high and low voluntary running
preference, allowing for a natural model of physical inactivity preference [64]. Koch and Britton
have similarly generated selective breeding models of high and low exercise capacity [65]. Both
of these models could be used to study the development of disease in the context of inactivity
and provide molecular targets for clinical research. This is also a more ethical approach, as elderly
humans undergoing bed-rest or step-reduction studies are accompanied with serious health con-
sequences as a result of these studies. Moving forward, clinical research must work in tandem with
molecular animal research to bring clarity to the current variability of bed-rest studies, specifically
regarding the metabolic responses to sedentary behavior. Current discrepancies could be ex-
plained by experimental design and controls, duration (short-term physiological responses to inac-
tivity versus pathological responses to chronic inactivity), differences in the age, sex, or race of the
participants, as well as their general health or prior activity levels. Future studies should take these
aspects into consideration as we continue to work towards improving our understanding of the
detrimental effects of physical inactivity and sedentary behavior.

Declaration of interests
No interests are declared.

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