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METABOLIC ADAPTATION TO INACTIVE LIFESTYLE:
FROM MUSCLE ATROPHY TO CARDIOVASCULAR RISK
Francesco AGOSTINI 1, Sara MAZZUCCO 1, Gianni BIOLO 1
1 University of Trieste (Italy), Department of Medical, Technological and Translational Sciences,
Division of Internal Medicine
Corresponding author:
Gianni Biolo
Clinica Medica, Ospedale di Cattinara, Strada di Fiume 447, Trieste 34149, Italy
e-mail: biolo@units.it
ABSTRACT
Inactivity is known to principally induce muscle atrophy, determined by unbalanced 
protein synthesis and degradation and to enhance general cardiovascular risk. In par-
allel, unloading can upregulate whole body oxidative stress and the action of antioxi-
dant factors, as physiological response. This alteration is accompanied by enhanced 
systemic infl ammation. Growing evidence in animal models suggest that infl ammation 
and oxidative stress can play a causative role in inactivity mediated muscle atrophy. The 
present review is focused on human studies linking inactivity mediated oxidative stress 
and infl ammation to unloading related atrophy. Recent works evidencing enhanced car-
diovascular risk after unloading are reported. In addition, evidence regarding the role 
of infl ammation in cardiovascular drawbacks linked to inactivity are discussed.
Keywords: physical inactivity, muscle atrophy, cardiovascular risk, infl ammation, 
oxidative stress
PRESNOVNE PRILAGODITVE NA NEAKTIVNI ŽIVLJENJSKI SLOG: OD 
MIŠIČNE ATROFIJE DO SRČNO-ŽILNEGA TVEGANJA
IZVLEČEK
Znano je, da neaktivnost povzroči predvsem mišično atrofi jo, ki jo zaznamuje ne-
ravnotežje med izgradnjo in razgradnjo beljakovin, in poveča splošno tveganje za 
srčno-žilne bolezni. Istočasno neaktivnost poviša oksidativni stres v celem telesu in 
kot fi ziološki odgovor nanje tudi delovanje antioksidativnih faktorjev. To spremembo 
review article UDC: 796.012:616.1:616.74
received: 2010-04-09
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spremlja povečano sistemsko vnetje. Vse več dokazov iz živalskih modelov kaže na to, 
da sta morda vnetje in oksidativni stres ključna za povzročitev mišične atrofi je kot po-
sledice neaktivnosti. Pričujoči pregledni članek se osredotoča na raziskave na ljudeh, 
ki povezujejo z neaktivnostjo povzročena oksidativni stres ter vnetje in z neaktivnostjo 
povezano mišično atrofi jo. Povzame tudi nedavne študije, ki ugotavljajo povečano srč-
no-žilno tveganje, povezano z neaktivnostjo. Poleg tega razpravlja tudi o vlogi vnetja 
pri srčno-žilnih težavah, povezanih z neaktivnostjo.
Ključne besede: gibalna/športna neaktivnost, mišična atrofi ja, srčno-žilno tveganje, 
vnetje, oksidativni stres
INTRODUCTION
The impact of physical activity level on human physiology has been intensively 
investigated during the last fi fty years. Physical exercise and in particular moderate 
training was demonstrated to play a positive role on health, such that the World Health 
Organization (WHO) is developing recommendations regarding required amount of 
physical activity in relation to age and gender (“Global recommendations on Physical 
Activity for Health” – WHO). On the contrary inactivity was shown to play a strongly 
negative role on human health, contributing to billions of deaths from chronic dis-
eases, and increasing prevalence of physical disabilities, especially in elderly people 
(Fontana, 2009). Immobility, or low activity, are frequent conditions, differentially as-
sociated to physiologic and pathologic states. Variably prolonged periods of inactivity 
can be due to several illness conditions: serious trauma and neurological diseases can 
preclude the possibility to walk or move, possibly leading to long term immobility. 
Equally, diseases belonging to internal medicine and cardiology, as well as all surgi-
cal interventions, often require prolonged recovery periods in the horizontal position. 
Finally, muscle inactivity also characterizes the spacefl ight microgravity environment 
where physical effort for initiating movements in the environment is drastically re-
duced. Notably, social changes occurring in the last years has led to the onset of the so 
called “sedentary lifestyle”, a severe reduction of average physical activity level, with 
undesired consequences in health (Chaput & Tremblay, 2009). All these conditions 
underline the importance of fully characterizing net effects of inactivity on physiology. 
To reach such aims the animal model of hindlimb unloading by tail suspension can be 
applied to rodents. Otherwise, in humans, experimental bed rest in healthy volunteers, 
beside lowerlimb casting, is the most accepted model to study physical inactivity: the 
net impact of physical inactivity, in fact, can not be assessed in hospitalized patients due 
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ANNALES KINESIOLOGIAE • 1 • 2010 • 1
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to the signifi cant contribution of the pathology. During bed rest studies human healthy 
volunteers lay in bed for different periods, performing all activities in the horizontal 
position. Bed rest studies, thus, allow to investigate in humans causes of metabolic and 
morphologic modifi cations occurring as a net consequence of physical inactivity.
Experimental bed rest was shown to signifi cantly modify the endocrine milieu 
(Biolo et al., 2005), and several studies showed bed rest signifi cantly induces skeletal 
muscle atrophy and cardiovascular alterations.
MUSCLE ATROPHY: MOLECULAR REGULATION OF PROTEIN SYNTHESIS 
AND DEGRADATION
Muscle atrophy is defi ned as a decrease of muscle mass. The maintenance of skel-
etal muscle mass is determined by the balance between protein synthesis and protein 
degradation. Clinical importance of muscle atrophy is underlined by poor prognosis 
characterizing cachectic patients in several setting of diseases (Deans & Wigmore et 
al., 2005). Different molecular mechanisms can control the rate of protein synthesis. 
Activation of factors of the Akt family (also called protein kinase B) is known to up-
regulate general protein synthesis in skeletal muscle: Akt factors are, in fact, serine/
threonine-specifi c protein kinases, playing a pivotal role in muscle hypertrophy (Bod-
ine, Latres et al., 2001). Activation of signaling cascades involving insulin-like growth 
factor 1 (IGF-1) and phosphatidylinositol 3-kinase (PI3K) induces Akt phosphorylation 
and activation (Bodine, Stitt et al., 2001). Akt, in turn, activates eukaryotic translation 
initiation factor 2B (eIF2B) by stimulation of glycogen synthase kinase-3 β (GSK-3 β) 
(Rhoads, 1999).
Several proteolytic systems, can contribute to the degradation of muscle proteins. In 
vitro and animal studies, showed Ca2+-activated proteases (Calpain) and the proteasome 
system play important roles in muscle protein breakdown during muscle atrophy (Pur-
intrapiban, Wang & Forsberg et al., 2003). Caspases may contribute to selected forms 
of muscle atrophy, releasing actin and myosin from actomyosin complexes, for subse-
quent degradation by the preoteasome system (Du et al., 2004). Two ubiquitin ligase 
enzymes as atrogin1 and muscle ring fi nger-1 (MuRF-1), were shown to be involved in 
skeletal muscle atrophy (Gomes, Lecker & Jagoe et al., 2001).
Bed rest and skeletal muscle atrophy
Several previous works showed that physical inactivity can signifi cantly affect mo-
lecular mediators of muscle atrophy. In the animal model of unloading, calpain activity 
was shown to be signifi cantly upregulated as an early event of muscle atrophy induction 
(Enns, Raastad & Ugelstad et al., 2007). On the contrary, artifi cial overexpression of 
calpastatin, a calpain inhibitor, preserved sarcomere structure and the force-generating 
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potential of unloaded murine muscles (Salazar, Michele & Brooks, et al., 2010). Ad-
ditional evidence in animal model showed that caspase-3 expression was increased in 
immobilized leg muscles: such modifi cation was accompanied by increased DNA frag-
mentation and consequent apoptosis induction (Nagano, Suzaki & Nagano et al., 2008). 
In humans, after 20 days of bed rest, an upregulation of atrogin-1-mediated muscle 
protein ubiquitination was demonstrated, confi rming the importance of the proteasome 
system for protein degradation secondary to immobility (Ogawa et al., 2006). Observa-
tions showing increased expression of molecular factors controlling muscle atrophy 
are confi rmed by publications directly showing in humans changes in muscle size and 
architecture secondary to bed rest. A bed rest period of 20 days signifi cantly induced a 
10 % thickness reduction in postural muscles (Akima et al., 2005). Eight weeks of bed 
rest similarly reduced by 14-17 % the cross sectional area of thigh and knee extensors 
(Ferretti et al., 2001). Thickness of postural calf muscles was shown to be decreased by 
9-12 % after 30 days of bed rest (Ellis, Kirby & Greenleaf , 1993) and a similar cross 
sectional area decrease was specifi cally shown in soleus and in gastrocnemius muscles 
after 1 month bed rest. (Berry, Berry, & Manelfe, 1993). Higher reduction (12-17 %) 
of cross sectional area of vastus intermedius (Ellis et al., 1993) was demonstrated after 
seven weeks of experimental bed rest. After extremely long term experimental periods 
(120 days) a 30 % decrease in calf muscle mass was measured (Leblanc et al., 1992). 
These and other published data demonstrate that the loss of lean body mass during pro-
longed periods of experimental inactivity in healthy volunteers, occurs at an average 
rate of 3-4% per week. This value is linearly maintained for the initial stages of the bed 
rest period, reaching a plateau after fi ve or six weeks.
Oxidative stress as potential trigger of muscle atrophy
Muscle wasting is an important clinical feature of several chronic diseases associ-
ated with oxidative stress as pathogenetic factor (Moylan & Reid, 2007). Oxidative 
stress stems from an unbalanced production of free radicals which is not suffi ciently 
scavenged by the activity of antioxidant defenses of the organism (Pastore, Federici & 
Bertini et al., 2003). Increased activity of antioxidant and cell damage repair systems 
can be evidenced after free radical production and oxidative stress onset (Hardmeier, 
Hoeger & Fang-Kircher et al., 1997). The most important non-enzymic antioxdant in 
the organism is glutathione: it is a thiolic tripeptide available in almost all human cells 
and synthesized by glutammic acid, cysteine and glycine (Pastore et al., 2003). 
Oxidative stress is known to be involved in the regulation of complex pathways lead-
ing to protein and muscle wasting. Oxidative stress can, in fact, induce intracellular ion-
ic calcium increase (Kondo, Nishino & Itokawa, 1994): interactions between oxidative 
stress and calcium availability changes can effectively trigger calpain action (Primeau, 
Adhihetty & Hood, 2002). Moreover, oxidative stress can induce skeletal muscle atro-
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phy indirectly triggering caspase-3 activity (Primeau et al., 2002). Otherwise, oxidative 
stress can directly affect muscle protein degradation at proteasome level: it, in fact, has 
been shown to upregulate the expression of muscle atrophy F-box/atrogin1 and MuRF-
1 in myotubes (Li, Chen & Li, et al., 2003). Increased expression of such E3 ubiquitin 
ligases in skeletal muscle can enhance proteolysis and muscle atrophy (Bodine, Latres 
et al., 2001). Action of free radicals on proteins is known to induce the modifi cation 
of selected amino acid (proline, arginine, lysine, and threonine) by stable addition of 
carbonyl groups (Roth, Manhart, & Wessner, 2004). Protein carbonylation, can lead to 
altered enzyme structure and activity (Stadtman, 2001). Increased levels of protein car-
bonylation were shown in patients affected by neurological diseases such as Alzheimer 
and Parkinson’s diseases, as well as on myopathies as Duchenne muscular dystrophy 
or amyotrophic lateral sclerosis (Stadtman, 2001). Carbonylation level was, previously 
demonstrated to be a reliable marker of oxidative stress occurrence (Greilberger et al., 
2008). There is evidence that oxidatively modifi ed proteins by carbonylation, can be se-
lectively degraded by the 20S core proteasome without ubiquitination (Grune, Merker 
& Sandig et al., 2003). In addition, to avoid accumulation of damaged peptides, carbon-
ylated proteins were shown to be more effi ciently scavenged by proteolytic degradation 
than their nonoxidized counterparts (Grune et al., 2003). Thus, enhanced muscle pro-
tein carbonylation can directly increase rate of protein degradation and muscle atrophy.
Inactivity and oxidative stress
Low levels of physical activity can promote oxidative stress onset: studies per-
formed in animals showed that regular housing, when compared to constant training, 
increased lipid peroxidation and ROS release (Laufs et al., 2005). Previously published 
evidence deriving from murine hindlimb unloading showed that inactivity can increase 
muscle oxidative stress with concomitantly impaired antioxidant defenses: in particu-
lar, experimental unloading increased, in soleus, lipid hydroperoxide levels and oxi-
dation of selected target substrates (Lawler, Song & Demaree, 2003). In addition, in 
unloaded soleus Cu,Zn-superoxide dismutase increased while, catalase and glutathione 
peroxidase, signifi cantly decreased, together with non-enzymatic antioxidant capacity 
(Lawler et al., 2003). Moreover, muscle unloading was shown to induce a decrease in 
antioxidant heat shock proteins as well as in glutathione peroxydase activity (Lawler 
et al., 2003). Otherwise, other published data showed that muscle unloading can up-
regulate heme-oxygenase response in virtue of a previously occurred oxidative damage 
(Hunter et al., 2001). Knowledge of direct links between oxidative stress and muscle 
inactivity is currently incomplete, but it seems plausible that inactivity can trigger free 
radicals production in muscle by interaction of at least fi ve different oxidant production 
pathways (Kondo, Nakagaki & Sasaki et al., 1993): 1) generation of ROS by the xan-
thine oxidase pathway (Whidden et al., 2009); 2) production of NO via increased NOS 
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activity (Kondo et al., 1993); 3) formation of ROS by increased cellular levels of reac-
tive iron (Kondo, Miura & Kodama et al., 1992) ; 4) potential activation of NADPH 
oxidase by increased availabitity of calcium through protein kinase C-ERK1/2 pathway 
(Javesghani, Magder & Barreiro et al., 2002) and 5) contribution of mitochondrial pro-
duction of superoxide radicals (Muller et al., 2007).
Role of oxidative stress on muscle atrophy following inactivity
Evidence suggests that inactivity mediated oxidative stress can promote muscle at-
rophy, as a typical consequence of immobility. An important work investigating, by 
microarray approach, alterations in gene expression of unloaded muscle, demonstrated 
that factors promoting oxidative stress as well as ubiquitination and protein degrada-
tion are signifi cantly upregulated by immobility (Stevenson, Giresi & Koncarevic et al., 
2003). As reviewed by Powers, Kavazis and McClung (2007), oxidative stress second-
ary to inactivity can effectively induce muscle atrophy activating specifi c proteolytic 
pathways and apoptosis processes. Interestingly, lowered oxidative stress induction in 
unloaded muscles, achieved by supplementation of antioxidant vitamin E, can reduce 
protein wasting and muscle atrophy (Appell, Duarte & Soares, 1997). Similarly, in an 
animal unloading study, vitamin A supplementation signifi cantly reduced muscle atro-
phy and lowered molecular mediators of protein degradation as calpain, caspases and 
the ubiquitin ligase MuRF-1 (Servais, Letexier & Favier et al., 2007).
The role of oxidative stress on physical inactivity mediated muscle atrophy was 
investigated in humans, within two bed rest studies organized in 2006 and 2007 at 
the Valdoltra Orthopaedic Hospital (University of Koper, Slovenia). Signifi cant muscle 
thickness and pennation angle reductions, as markers of enhanced muscle atrophy, were 
observed in Vastus lateralis muscle at the end of the experimental period (de Boer et al., 
2008). Increased bed rest mediated muscle protein carbonylation was shown, in parallel 
with an early stage upregulation of the antioxidant protein Heme Oxygenase-1 (Dalla 
Libera et al., 2009). As abovementioned, in fact, protein carbonylation was shown to be 
a key factor enhancing direct protein degradation by the proteasome system (Grune et 
al., 2003): thus, increased carbonylation levels can be considered one of the a mecha-
nistic causes contributing to protein wasting and muscle atrophy. In a recent publication 
(Agostini et al., 2010) we showed, by a novel validated method involving a single biop-
sy and double infusion of isotopic tracers, that i) glutathione synthesis rate was upregu-
lated in muscle after inactivity as response to tissutal oxidative stress and ii) that such 
change was signifi cantly correlated to the atrophy level. Moreover, enhanced whole 
body infl ammation and oxidative stress mediated by fat mass gain during bed rest was 
associated to a marked increase of muscle atrophy mediated by inactivity (Biolo et al., 
2008). Such observations further underline that oxidative stress could be involved in 
muscle atrophy induction following inactivity in humans.
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Infl ammation as additional mechanism of muscle atrophy
Previous evidence showed a direct link between infl ammation and muscle atrophy. 
Muscle mass wasting normally occurring in healthy aging subjects was demonstrated 
to occur as a consequence of increased infl ammation (Jensen, 2008). 
Deregulation of pro- and anti-infl ammatory cytokines or mediators was signifi cant-
ly associated to the activation of muscle wasting process. In particular upregulation of 
IL-1, IL-6 and tumor necrosis factor-alpha was previously shown to potentially trigger 
muscle sarcopenia in elderly subjects (Yende et al., 2006). In addition, an interesting 
study based on DNA microarray analysis showed that a subgroup of genes involved in 
promotion of infl ammation was upregulated in sarcopenic elderly subjects (Giresi et 
al., 2005). Prolonged or chronic infl ammation is also associated to specifi c pathologies 
linked to muscle atrophy. Previously published studies underlined that infl ammation can 
be a possible cause of cancer cachexia: proinfl ammatory tumor necrosis factor alpha, 
known also as cachectin, was shown to be one of the factors triggering hypercatabolic 
processes in tumor bearing subjects (Tracey & Cerami, 1994). Tumor necrosis factor 
alpha, was shown in cellular model to increase total protein loss, total ubiquitination 
and activation of NF-kB: interestingly the process was demonstrated to be triggered by 
endogenous production of ROS (Kramer & Goodyear, 2007). Thus, infl ammation can 
be considered as a potential mechanism triggering muscle atrophy in healthy subjects.
Effects of inactivity on infl ammation
Immobility was demonstrated to worsen the infl ammatory condition. An observa-
tional study performed in a large sample of male and female subjects showed that per-
sons adopting an unhealthy sedentary lifestyle were characterized by mildly increased 
levels of C-reactive protein (CRP), a marker of low grade infl ammation: interestingly, 
appropriate moderate training programs and the so called “mediterranean diet” reduced 
the observed CRP increase (Pitsavos et al., 2007). Another epidemiologic study con-
fi rmed that, regardless of the degree of obesity, sedentary lifestyle is associated with in-
creased levels of interleukin-6 and of CRP (Fischer, Berntsen & Perstrup, 2007). Addi-
tionally, published evidence (Bosutti et al., 2008) showed in humans that experimental 
bed rest can increase infl ammation upregulating CRP levels and ratio between IL-6 and 
IL-10 cytokines. Eicosanoids, including prostaglandines tromboxanes and leukotrienes 
are regulators of infl ammatory factors (Lewis, Austen & Soberman, 1990). Polyunsatu-
rated fatty acids (PUFA) of the n-6 series and in particular arachidonic acid are known 
to be eicosanoid precursors: elevated availability of n-6 PUFA in cell membranes was 
previously linked to infl ammatory diseases (Ueda et al., 2008). By contrast, the n-3 
PUFA series is characterized by a signifi cant anti-infl ammatory action. Phospholipid 
content in red blood cell membranes can be considered a reliable marker of whole 
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body infl ammation status, of fatty acid availability in plasma, and of cell membrane 
composition of the whole body (Harris & Von Schacky, 2004). The effect of physical 
inactivity on infl ammation and membrane fatty acid composition, was investigated in 
three bed rest studies performed at the Valdoltra Orthopaedic Hospital, (University of 
Koper, Slovenia) in 2006, 2007 and 2008. Results (Mazzucco, Agostini & Biolo, 2010) 
displayed monounsaturated fatty acids total content was signifi cantly reduced together 
with-linolenic and eicosapentaenoic acid levels. Otherwise, bed rest enhanced specifi c 
n-6 PUFA content and in particular, the arachidonic-to-eicosapentaenoic acid ratio was 
signifi cantly increased after bed rest. In parallel, bed rest enhanced whole body infl am-
mation reducing n-3 PUFA fraction in cell membranes. Thus, a signifi cant bed rest 
mediated shift toward a proinfl ammatory pattern could be demonstrated (Mazzucco, et 
al., 2010). These observations are in accordance with previously published data show-
ing the pro-infl ammatory effect of bed rest at whole body level (Bosutti et al., 2008).
In conclusion, considering the potential of infl ammation to stimulate muscle wast-
ing, increased infl ammation mediated by bed rest can reliably provide an additional 
mechanism explaining the inactivity mediated induction of sarcopenia.
Cardiovascular consequences of inactivity: role of infl ammation and oxidative 
stress
Different studies demonstrated a strong relationship between inactive lifestyle and 
cardiovascular risk in terms of increased diabetes (Fretts et al., 2009) and coronary ar-
tery disease (Boekholdt et al., 2006) incidence. Noteworthy, inactive lifestyle is known 
to be per se the primary underlying cause of metabolic syndrome (Zhu, St Onge & Hes-
hka et al., 2004). Apart from epidemiologic studies, direct evidence directly linking in-
activity and cardiovascular alterations derives from previous bed rest studies. Reported 
data showed that several cardiac functional parameters, as isovolumic relaxation time 
and myocardial performance were negatively affected by bed rest (Platts et al., 2009) 
suggesting a direct role of unloading on heart muscle effi ciency. The effects of bed rest 
on cardiac muscle morphology and function were previously observed in 24 healthy 
young women by magnetic resonance imaging: signifi cant reductions in left and right 
ventricular volumes and masses were observed as markers of cardiac atrophy leading to 
reduced standing stroke volume and orthostatic tolerance (Dorfman et al., 2007). This 
further confi rms that experimental bed rest can directly impair cardiac muscle morphol-
ogy and function. Internal fl uids redistribution determined by changed position from 
the orthostatic to the supine position was shown to account for reduced blood pressure, 
heart rate variability and baroreceptor refl ex sensitivity after bed rest, showing that 
physical inactivity impairs autonomic regulation of cardiovascular system (Ferretti et 
al., 2009). In a previously published work, 56 days of bed rest induced a signifi cant det-
rimental role on the cardiovascular system increasing markers of endothelial damage 
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(Demiot et al., 2007). Infl ammation was shown to play a key role in the development 
of cardiovascular pathologies (Boekholdt et al., 2006) and, in parallel, infl ammation is 
considered to be one of the pathogenetic factors of a cardiometabolic illness as diabetes 
(Duncan & Schmidt, 2006). Additionally, low grade chronic infl ammation is a known 
cardiovascular risk marker: a relation, in fact, between increased CRP levels and risk 
of metabolic syndrome onset was shown (Devaraj, Singh & Jialal, 2009) and, interest-
ingly, previously published data demonstrated that increased n-6 to n-3 PUFA ratio 
can be related to worsened mortality for cardiovascular causes (Harris & Von Schacky, 
2004). Previously mentioned publications showed that bed rest can lead to worsened 
infl ammatory condition in terms of upregulated ratio between n-6 and n-3 PUFA (Maz-
zucco et al., 2010) as well as of augmented CRP synthesis (Bosutti et al., 2008): thus, 
experimental physical inactivity can effectively induce an enhancement of cardiovas-
cular risk. Interestingly, proinfl ammatory changes in fatty acid membrane composi-
tion were paralleled by increased HOMA index for insulin resistance (Mazzucco et 
al., 2010). These results suggest that during physical inactivity increased infl ammation 
can contribute to an important metabolic alteration related to cardiovascular system as 
insulin resistance.
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