• Francesco Agostini University of Trieste, Department of Medical, Technological and Translational Sciences, Division of Internal Medicine
  • Sara Mazzucco University of Trieste, Department of Medical, Technological and Translational Sciences, Division of Internal Medicine
  • Gianni Biolo University of Trieste, Department of Medical, Technological and Translational Sciences, Division of Internal Medicine


Inactivity is known to principally induce muscle atrophy, determined by unbalanced protein synthesis and degradation and to enhance general cardiovascular risk. In parallel, unloading can upregulate whole body oxidative stress and the action of antioxidant factors, as physiological response. This alteration is accompanied by enhanced systemic inflammation. Growing evidence in animal models suggest that inflammation 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 inflammation to unloading related atrophy. Recent works evidencing enhanced cardiovascular risk after unloading are reported. In addition, evidence regarding the role of inflammation in cardiovascular drawbacks linked to inactivity are discussed.


Agostini, F., Dalla Libera, L., Rittweger, J., Mazzucco, S., Jurdana, M., Mekjavic, I.B., Pišot, R., Gorza, L., Narici, M., & Biolo, G. (in print). Effects of inactivity on human muscle glutathione synthesis by a double-tracer and single-biopsy approach. The journal of physiology.

Akima, H., Katayama, K., Sato, K., Ishida, K., Masuda, K., Takada, H., Watanabe,Y., & Iwase, S. (2005). Intensive cycle training with artificial gravity maintains muscle size during bed rest. Aviation, space, and environmental medicine, 76(10), 923-929.

Appell, H.J., Duarte, J.A., & Soares, J.M. (1997). Supplementation of vitamin E may attenuate skeletal muscle immobilization atrophy. International Journal of Sports Medicine, 18(3), 157-160.

Berry, P., Berry, I., & Manelfe, C. (1993). Magnetic resonance imaging evaluation of lower limb muscles during bed rest-a microgravity simulation model. Aviation, space, and environmental medicine, 64(1), 212-218.

Biolo, G., Agostini, F., Simunic, B., Sturma, M., Torelli, L., Preiser, J.C., Deby-Dupont, G., Magni, P., Strollo, F., di Prampero, P., Guarnieri, G., Mekjavic, I.B., Pisot, R., & Narici, M.V. (2008). Positive energy balance is associated with accelerated muscle atrophy and increased erythrocyte glutathione turnover during 5 wk of bed rest. American journal of clinical nutrition, 88(4), 950-958.

Biolo, G., Ciocchi, B., Stulle, M., Piccoli, A., Lorenzon, S., Dal Mas, V., Barazzoni, R., Zanetti, M., & Guarnieri,G. (2005). Metabolic consequences of physical inactivity. Journal of renal nutrition, 15(1), 49-53.

Bodine, S. C., Latres, E., Baumhueter, S., Lai, V. K., Nunez, L., Clarke, B. A., Poueymirou, W. T., Panaro, F. J., Na, E., Dharmarajan, K., Pan, Z. Q., Valenzuela, D. M., DeChiara, T. M., Stitt, T. N., Yancopoulos, G. D., & Glass, D. J. (2001). Identification of ubiquitin ligases required for skeletal muscle atrophy. Science, 294(5547), 1704-1708.

Bodine, S. C., Stitt, T. N., Gonzalez, M., Kline, W. O., Stover, G. L., Bauerlein, R., Zlotchenko, E., Scrimgeour, A., Lawrence, J. C., Glass, D. J., & Yancopoulos, G. D. (2001). Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nature cell biology, 3(11), 1014-1019.

Boekholdt, S. M., Sandhu, M. S., Day, N. E., Luben, R., Bingham, S. A., Peters, R. J., Wareham, N. J., & Khaw, K. T. (2006). Physical activity, C-reactive protein levels and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk prospective population study. European journal of cardiovascular prevention & rehabilitation, 13(6), 970-976.

Bosutti, A., Malaponte, G., Zanetti, M., Castellino, P., Heer, M., Guarnieri, G., & Biolo, G. (2008). Calorie restriction modulates inactivity-induced changes in the inflammatory markers C-reactive protein and pentraxin-3. Journal of clinical endocrinology and metabolism., 93(8), 3226-3229.

Chaput, J. P., & Tremblay, A. (2009). Obesity and Physical Inactivity: The Relevance of Reconsidering the Notion of Sedentariness. Obesity facts, 2(4), 249-254.

Dalla Libera, L., Ravara, B., Gobbo,V., Tarricone, E., Vitadello, M., Biolo, G., Vescovo, G., & Gorza, L. (2009). A transient antioxidant stress response accompanies the onset of disuse atrophy in human skeletal muscle. Journal of applied physiology, 107(2), 549-557.

de Boer, M.D., Seynnes, O.R., di Prampero, P.E., Pisot, R., Mekjavić, I.B., Biolo, G., & Narici, M.V. (2008). Effect of 5 weeks horizontal bed rest on human muscle thickness and architecture of weight bearing and non-weight bearing muscles. European journal of applied physiology., 104(2), 401-407.

Deans C., & Wigmore S.J. (2005). Systemic inflammation, cachexia and prognosis in patients with cancer. Current Opinion in Clinical Nutrition & Metabolic Care, 8(3), 265-269.

Demiot C., Dignat-George F., Fortrat J.O., Sabatier F., Gharib C., Larina I., Gauquelin-Koch G., & Hughson R., Custaud M.A. (2007). WISE 2005: chronic bed rest impairs microcirculatory endothelium in women. American journal of physiology – Heart and circulatory physiology, 293(5), 3159-3164.

Devaraj, S., Singh, U., & Jialal, I. (2009). Human C-reactive protein and the metabolic syndrome (Review). Current opinion in lipidology, 20(3), 182-189.

Dorfman, T.A., Levine, B.D., Tillery, T., Peshock, R.M., Hastings, J.L., Schneider, S.M., Macias, B.R., Biolo, G., & Hargens, A.R. (2007). Cardiac atrophy in women following bed rest. Journal of applied physiology, 103(1), 8-16.

Du, J., Wang, X., Miereles, C., Bailey, J.L., Debigare, R., Zheng, B., Price, S.R., & Mitch, W.E. (2004). Activation of caspase-3 is an initial step triggering accelerated muscle proteolysis in catabolic conditions. Journal of clinical investigations, 113(1), 115-123.

Duncan, B.B., & Schmidt, M.I. (2006). The epidemiology of low-grade chronic systemic inflammation and type 2 diabetes. Diabetes technology & therapeutics, 8(1), 7-17.

Ellis, S., Kirby, L.C., & Greenleaf, J.E. (1993). Lower extremity muscle thickness during 30-day 6 degrees head-down bed rest with isotonic and isokinetic exercise training. Aviation, space, and environmental medicine, 64(11), 1011-1015.

Enns, D.L., Raastad, T., Ugelstad, I., & Belcastro, A.N. (2007). Calpain/calpastatin activities and substrate depletion patterns during hindlimb unweighting and reweighting in skeletal muscle. European journal of applied physiology., 100(4), 445-455

Ferretti, G., Iellamo, F., Pizzinelli, P., Kenfack, M.A., Lador, F., Lucini, D., Porta, A., Narkiewicz, K., & Pagani, M. (2009). Prolonged head down bed rest-induced inactivity impairs tonic autonomic regulation while sparing oscillatory cardiovascular rhythms in healthy humans. Journal of hypertension, 27(3), 51-61.

Ferretti, G., Berg, H.E., Minetti, A.E., Moia, C., Rampichini, S., & Narici, M.V. (2001). Maximal instantaneous muscular power after prolonged bed rest in humans. Journal of applied physiology, 90(2), 431-435.

Fischer, C.P., Berntsen, A., Perstrup, L.B., Eskildsen, P., & Pedersen, B.K. (2007). Plasma levels of interleukin-6 and C-reactive protein are associated with physical inactivity independent of obesity. Scandinavian journal of medicine and science in sports., 17(5), 580-587.

Fontana, L. (2009). Modulating human aging and age-associated diseases. Biochimica et biophysica acta, 1790(10), 1133-1138.

Fretts, A.M., Howard, B.V., Kriska, A.M, Smith, N.L., Lumley, T., Lee, E.T., Russell, M., & Siscovick, D. (2009). Physical activity and incident diabetes in American Indians: the Strong Heart Study. American journal of epidemiology, 170(5), 632-639.

Giresi, P.G., Stevenson, E.J., Theilhaber, J., Koncarevic, A., Parkington, J., Fielding, R.A., & Kandarian, S.C. (2005). Identification of a molecular signature of sarcopenia. Physiological genomics, 21(2), 253-263.

Gomes, M.D., Lecker, S.H., Jagoe, R.T., Navon, A., & Goldberg, A.L. (2001). Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proceedings of the National academy of sciences of the United States of America, 98(25), 14440-14445.

Greilberger, J., Koidl, C., Greilberger, M., Lamprecht, M., Schroecksnadel, K., Leblhuber, F., Fuchs, D., & Oettl, K. (2008). Malondialdehyde, carbonyl proteins and albumin-disulphide as useful oxidative markers in mild cognitive impairment and Alzheimer's disease. Free Radical Research, 42(7), 633-638.

Grune, T., Merker, K., Sandig, G., & Davies, K.J. (2003). Selective degradation of oxidatively modified protein substrates by the proteasome. Biochemical and biophysical research communications., 305(3), 709-718.

Hardmeier, R., Hoeger, H., Fang-Kircher, S., Khoschsorur, A., & Lubec, G. (1997). Transcription and activity of antioxidant enzymes after ionizing irradiation in radiation-resistant and radiation-sensitive mice. Proceedings of the National academy of sciences of the United States of America, 94(14), 7572-7576.

Harris, W.S., & Von Schacky, C. (2004). The Omega-3 Index: a new risk factor for death from coronary heart disease? Preventive medicine, 39(1), 212-220.

Javesghani, D., Magder, S.A., Barreiro, E., Quinn, M.T., & Hussain, S.N. (2002). Molecular characterization of a superoxide-generating NAD(P)H oxidase in the ventilatory muscles. American journal of respiratory and critical care medicine, 165(3), 412-418.

Jensen, G.L. (2008). Inflammation: roles in aging and sarcopenia. Journal of parenteral and enteral nutrition, 32(6), 656-659.

Kondo, H., Miura, M., Kodama, J., Ahmed, S.M., & Itokawa, Y. (1992). Role of iron in oxidative stress in skeletal muscle atrophied by immobilization. Pflugers Archiv. 421(2-3), 295-297.

Kondo, H., Nakagaki, I., Sasaki, S., Hori, S., & Itokawa, Y. (1993). Mechanism of oxidative stress in skeletal muscle atrophied by immobilization. American journal of physiology, 265(6 pt 1), E839-E844.

Kondo, H., Nishino, K., & Itokawa, Y. (1994). Hydroxyl radical generation in skeletal muscle atrophied by immobilization. FEBS Letters, 349(2), 169-172.

Kramer, H.F., & Goodyear, L.J. (2007). Exercise, MAPK, and NF-kappaB signaling in skeletal muscle. Journal of applied physiology, 103(1), 388-395.

Laufs, U., Wassmann, S., Czech, T., Munzel, T., Eisenhauer, M., Bohm, M., & Nickenig, G. (2005). Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis. Arteriosclerosis thrombosis and vascular biology, 25(4), 809-814.

Lawler, J.M., Song, W., & Demaree, S.R. (2003). Hindlimb unloading increases oxidative stress and disrupts antioxidant capacity in skeletal muscle. Free radical biology and medicine, 35(1), 9-16.

Leblanc, A.D., Schneider, V.S., Evans, H.J., Pientok, C., Rowe, R., & Spector, E. (1992). Regional changes in muscle mass following 17 weeks of bed rest. Journal of applied physiology, 73(5), 2172-2178.

Lewis, R.A., Austen, K.F., & Soberman, R.J. (1990). Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases. The New England Journal of Mededicine., 323(10), 645-655.

Li, Y.P., Chen, Y., Li, A.S., & Reid, M.B. (2003). Hydrogen peroxide stimulates ubiquitin-conjugating activity and expression of genes for specific E2 and E3 proteins in skeletal muscle myotubes. American journal of physiology – Cell physiology., 285(4), C806-C812.

Mazzucco, S., Agostini, F., & Biolo, G. (2010). Inactivity-mediated insulin resistance is associated with upregulated pro-inflammatory fatty acids in human cell membranes. Clinical Nutrition., 29(3), 386-90.

Moylan, J.S., & Reid, M.B. (2007). Oxidative stress, chronic disease, and muscle wasting. Muscle & Nerve, 35(4), 411-429.

Muller, F.L., Song, W., Jang, Y.C., Liu, Y., Sabia, M., Richardson, A., & Van Remmen, H. (2007). Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. American journal of physiology - Regulatory, integrative and comparative physiology, 293(3), R1159-R1168.

Nagano, K., Suzaki, E., Nagano, Y., Kataoka, K., & Ozawa, K. (2008). The activation of apoptosis factor in hindlimb unloading-induced muscle atrophy under normal and low-temperature environmental conditions. Acta Histochemica, 110(6), 505-618.

Ogawa, T., Furochi, H., Mameoka, M., Hirasaka, K., Onishi, Y., Suzue, N., Oarada, M., Akamatsu, M., Akima, H., Fukunaga, T., Kishi, K., Yasui, N., Ishidoh, K., Fukuoka, H., Nikawa, T. (2006). Ubiquitin ligase gene expression in healthy volunteers with 20-day bedrest. Muscle & Nerve, 34(4), 463-469.

Pastore, A., Federici, G., Bestini, E., & Piemonte, F. (2003). Analysis of glutathione: implication in redox and detoxification. Clinica chimica acta, 333(1), 19-39.

Pitsavos, C., Panagiotakos, D.B., Tzima, N., Lentzas, Y., Chrysohoou, C., Das, U.N., & Stefanadis, C. (2007). Diet, exercise, and C-reactive protein levels in people with abdominal obesity: the ATTICA epidemiological study. Angiology, 58(2), 225-233.

Platts, S.H., Martin, D.S., Stenger, M.B., Perez, S.A., Ribeiro, L.C., Summers, R., & Meck, J.V. (2009). Cardiovascular adaptations to long-duration head-down bed rest. Aviation, space and environmental medicine, 80(5 Suppl), A29-A36.

Powers, S.K., Kavazis, A.N., & McClung, J.M. (2007). Oxidative stress and disuse muscle atrophy. Journal of applied physiology, 102(6), 2389-2397.

Primeau, A.J., Adhihetty, P.J., & Hood, D.A. (2002). Apoptosis in heart and skeletal muscle. Canadian journal of applied physiology, 27(4), 349-395.

Purintrapiban, J., Wang, M.C., & Forsberg, N.E. (2003). Degradation of sarcomeric and cytoskeletal proteins in cultured skeletal muscle cells. Comparative biochemistry and physiology part B: biochemistry and molecular biology, 136(3), 393-401.

Rhoads, R.E. (1999). Signal transduction pathways that regulate eukaryotic protein synthesis. Journal of biological cheistry, 274(43), 30337-30340.

Roth, E., Manhart, N., & Wessner, B. (2004). Assessing the antioxidative status in critically ill patients. Current opinion in clinical nutrition and metabolic care, 7(2), 161-168.

Salazar, J.J., Michele, D.E., & Brooks, S.V. (2010). Inhibition of calpain prevents muscle weakness and disruption of sarcomere structure during hindlimb suspension. Journal of applied physiology, 108(1), 120-127.

Servais, S., Letexier, D., Favier, R., Duchamp, C., & Desplanches, D. (2007). Prevention of unloading-induced atrophy by vitamin E supplementation: links between oxidative stress and soleus muscle proteolysis? Free radical biology and medicine, 42(5), 627-635.

Stadtman, E.R. (2001). Protein oxidation in aging and age-related diseases. Annals of the New York academy of sciences, 928, 22-38.

Stevenson, E.J., Giresi, P.G., Koncarevic, A., & Kandarian, S.C. (2003). Global analysis of gene expression patterns during disuse atrophy in rat skeletal muscle. Journal of physiology, 551(Pt 1), 33-48.

Tracey, K.J., & Cerami, A. (1990). Metabolic responses to cachectin/TNF. A brief review. Annals of the New York academy of sciences., 587, 325-331.

Ueda, Y., Kawakami, Y., Kunii, D., Okada, H., Azuma, M., Le, D.S., & Yamamoto, S. (2008). Elevated concentrations of linoleic acid in erythrocyte membrane phospholipids in patients with inflammatory bowel disease. Nutrition research, 28(4), 239-244.

Whidden, M.A., McClung, J.M., Falk, D.J., Hudson, M.B., Smuder, A.J., Nelson, W.B., & Powers, S.K. (2009). Xanthine oxidase contributes to mechanical ventilation-induced diaphragmatic oxidative stress and contractile dysfunction. Journal of applied physiology, 106(2), 385-394.

Yende, S., Waterer, G.W., Tolley, E.A., Newman, A.B., Bauer, D.C., Taaffe, D.R., Jensen, R., Crapo, R., Rubin, S., Nevitt, M., Simonsick, E.M., Satterfield, S., Harris, T., & Kritchevsky, S.B. (2006). Inflammatory markers are associated with ventilatory limitation and muscle dysfunction in obstructive lung disease in well functioning elderly subjects. Thorax, 61(1), 10-16.

Zhu, S., St Onge, M.P., Heshka, S., & Heymsfield, S.B. (2004). Lifestyle behaviors associated with lower risk of having the metabolic syndrome. Metabolism, 53(11), 1503-1511.


How to Cite

Agostini, F., Mazzucco, S., & Biolo, G. (2015). METABOLIC ADAPTATION TO INACTIVE LIFESTYLE: FROM MUSCLE ATROPHY TO CARDIOVASCULAR RISK. Annales Kinesiologiae, 1(1). Retrieved from