Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Weakness of whole muscles in mice deficient in Cu, Zn superoxide dismutase is not explained by defects at the level of the contractile apparatus


Mice deficient in Cu,Zn superoxide dismutase (Sod1 / mice) demonstrate elevated oxidative stress associated with rapid age-related declines in muscle mass and force. The decline in mass for muscles of Sod1 / mice is explained by a loss of muscle fibers, but the mechanism underlying the weakness is not clear. We hypothesized that the reduced maximum isometric force (F o) normalized by cross-sectional area (specific F o) for whole muscles of Sod1 / compared with wild-type (WT) mice is due to decreased specific F o of individual fibers. Force generation was measured for permeabilized fibers from muscles of Sod1 / and WT mice at 8 and 20 months of age. WT mice were also studied at 28 months to determine whether any deficits observed for fibers from Sod1 / mice were similar to those observed in old WT mice. No effects of genotype were observed for F o or specific F o at either 8 or 20 months, and no age-associated decrease in specific F o was observed for fibers from Sod1 / mice, whereas specific F o for fibers of WT mice decreased by 20 % by 28 months. Oxidative stress has also been associated with decreased maximum velocity of shortening (V max), and we found a 10 % lower V max for fibers from Sod1 /compared with WT mice at 20 months. We conclude that the low specific F o of muscles of Sod1 / mice is not explained by damage to contractile proteins. Moreover, the properties of fibers of Sod1 / mice do not recapitulate those observed with aging in WT animals.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. Andrade FH, Reid MB, Allen DG, Westerblad H (1998) Effect of hydrogen peroxide and dithiothreitol on contractile function of single skeletal muscle fibres from the mouse. J Physiol 509:565–575

  2. Andrade FH, Reid MB, Westerblad H (2001) Contractile response of skeletal muscle to low peroxide concentrations: myofibrillar calcium sensitivity as a likely target for redox- modulation. FASEB J 15:309–311

  3. Brooks SV, Faulkner JA (1988) Contractile properties of skeletal muscles from young, adult and aged mice. J Physiol 404:71–82

  4. Burkholder TJ, Fingado B, Baron S, Lieber RL (1994) Relationship between muscle fiber types and sizes and muscle architectural properties in the mouse hindlimb. J Morphol 221:177–190

  5. Callahan LA, She ZW, Nosek TM (2001) Superoxide, hydroxyl radical, and hydrogen peroxide effects on single-diaphragm fiber contractile apparatus. J Appl Physiol 90:45–54

  6. Claflin DR, Larkin LM, Cederna PS, Horowitz JF, Alexander NB, Cole NM, Galecki AT, Chen S, Nyquist LV, Carlson BM, Faulkner JA, Ashton-Miller JA (2011) Effects of high- and low-velocity resistance training on the contractile properties of skeletal muscle fibers from young and older humans. J Appl Physiol 111:1021–1030

  7. Coombes JS, Powers SK, Rowell B, Hamilton KL, Dodd SL, Shanely RA, Sen CK, Packer L (2001) Effects of vitamin E and alpha-lipoic acid on skeletal muscle contractile properties. J Appl Physiol 90:1424–1430

  8. Darnley GM, Duke AM, Steele DS, MacFarlane NG (2001) Effects of reactive oxygen species on aspects of excitation-contraction coupling in chemically skinned rabbit diaphragm muscle fibres. Exp Physiol 86:161–168

  9. Degens H, Yu F, Li X, Larsson L (1998) Effects of age and gender on shortening velocity and myosin isoforms in single rat muscle fibres. Acta Physiol Scand 163:33–40

  10. Dutka TL, Mollica JP, Lamb GD (2011) Differential effects of peroxynitrite on contractile protein properties in fast- and slow-twitch skeletal muscle fibers of rat. J Appl Physiol 110:705–716

  11. Fulle S, Protasi F, Di TG, Pietrangelo T, Beltramin A, Boncompagni S, Vecchiet L, Fano G (2004) The contribution of reactive oxygen species to sarcopenia and muscle ageing. Exp Gerontol 39:17–24

  12. Gonzalez E, Messi ML, Delbono O (2000) The specific force of single intact extensor digitorum longus and soleus mouse muscle fibers declines with aging. J Membr Biol 178:175–183

  13. Jackson MJ (2009) Skeletal muscle aging: role of reactive oxygen species. Crit Care Med 37:S368–S371

  14. Jackson MJ, McArdle A (2011) Age-related changes in skeletal muscle reactive oxygen species generation and adaptive responses to reactive oxygen species. J Physiol 589:2139–2145

  15. Jang YC, Lustgarten MS, Liu Y, Muller FL, Bhattacharya A, Liang H, Salmon AB, Brooks SV, Larkin L, Hayworth CR, Richardson A, Van Remmen H (2010) Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration. FASEB J 24:1376–1390

  16. Ji LL (2007) Antioxidant signaling in skeletal muscle: a brief review. Exp Gerontol 42:582–593

  17. Ji LL (2008) Modulation of skeletal muscle antioxidant defense by exercise: role of redox signaling. Free Radic Biol Med 44:142–152

  18. Ji LL, Gomez-Cabrera MC, Vina J (2009) Role of free radicals and antioxidant signaling in skeletal muscle health and pathology. Infect Disord Drug Targets 9:428–444

  19. Jimenez-Moreno R, Wang ZM, Gerring RC, Delbono O (2008) Sarcoplasmic reticulum Ca2+ release declines in muscle fibers from aging mice. Biophys J 94:3178–3188

  20. Lamb GD, Posterino GS (2003) Effects of oxidation and reduction on contractile function in skeletal muscle fibres of the rat. J Physiol 546:149–163

  21. Larkin LM, Davis CS, Sims-Robinson C, Kostrominova TY, Van Remmen H, Richardson A, Feldman EL, Brooks SV (2011) Skeletal muscle weakness due to deficiency of CuZn superoxide dismutase is associated with loss of functional innervation. Am J Physiol Regul Integr Comp Physiol 301(5):R1400–7

  22. Larsson L, Li X, Frontera WR (1997) Effects of aging on shortnening velocity and myosin isoform composition in single human skeletal muscle cells. Am J Physiol Cell Physiol 272:C638–C649

  23. Li X, Larsson L (1996) Maximum shortening velocity and myosin isoforms in single muscle fibers from young and old rats. Am J Physiol Cell Physiol 270:C352–C360

  24. Li X, Moody MR, Engel D, Walker S, Clubb FJ Jr, Sivasubramanian N, Mann DL, Reid MB (2000) Cardiac-specific overexpression of tumor necrosis factor-alpha causes oxidative stress and contractile dysfunction in mouse diaphragm. Circulation 102:1690–1696

  25. Lowe DA, Surek JT, Thomas DD, Thompson LV (2001) Electron paramagnetic resonance reveals age-related myosin structural changes in rat skeletal muscle fibers. Am J Physiol (Cell) 280:C540–C547

  26. Moisescu DG, Thieleczek R (1978) Calcium and strontium concentration changes within skinned muscle preparations following a change in the external bathing solution. J Physiol 275:241–262

  27. Muller FL, Song W, Liu Y, Chaudhuri A, Pieke-Dahl S, Strong R, Huang TT, Epstein CJ, Roberts LJ, Csete M, Faulkner JA, Van Remmen H (2006) Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy. Free Radic Biol Med 40:1993–2004

  28. Panchangam A, Witte RS, Claflin DR, O'Donnell M, Faulkner JA (2006) A novel optical imaging system for investigating sarcomere dynamics in single skeletal muscle fibers. Proceedings of the SPIE 6088(1):608808–608811

  29. Plant DR, Lynch GS, Williams DA (2000) Hydrogen peroxide modulates Ca2 + -activation of single permeabilized fibres from fast- and slow-twitch skeletal muscles of rats. J Muscle Res Cell Mot 21:747–752

  30. Plant DR, Gregorevic P, Williams DA, Lynch GS (2001) Redox modulation of maximum force production of fast-and slow-twitch skeletal muscles of rats and mice. J Appl Physiol 90:832–838

  31. Podolin RA, Ford LE (1986) Influence of partial activation on force-velocity propoerties of frog skinned muscle fibers in millimolar magnesium ion. J Gen Physiol 87:607–631

  32. Prochniewicz E, Lowe DA, Spakowicz DJ, Higgins L, O'Conor K, Thompson LV, Ferrington DA, Thomas DD (2008) Functional, structural, and chemical changes in myosin associated with hydrogen peroxide treatment of skeletal muscle fibers. Am J Physiol (Cell) 294:C613–C626

  33. Reid MB (2001) Invited review: redox modulation of skeletal muscle contraction: what we know and what we don't. J Appl Physiol 90:724–731

  34. Reid MB, Khawli FA, Moody MR (1993) Reactive oxygen in skeletal muscle. III. Contractility of unfatigued muscle. J Appl Physiol 75:1081–1087

  35. Sakellariou GK, Pye D, Vasilaki A, Zibrik L, Palomero J, Kabayo T, McArdle F, Van Remmen H, Richardson A, Tidball JG, McArdle A, Jackson MJ (2011) Role of superoxide-nitric oxide interactions in the accelerated age-related loss of muscle mass in mice lacking Cu, Zn superoxide dismutase. Aging Cell 10:749–760

  36. Supinski GS, Callahan LA (2007) Free radical-mediated skeletal muscle dysfunction in inflammatory conditions. J Appl Physiol 102:2056–2063

  37. Supinski G, Stofan D, Callahan LA, Nethery D, Nosek TM, Dimarco A (1999) Peroxynitrite induces contractile dysfunction and lipid peroxidation in the diaphragm. J Appl Physiol 87:783–791

  38. Thompson LV (2009) Age-related muscle dysfunction. Exp Gerontol 44:106–111

  39. Vasilaki A, van der Meulen JH, Larkin L, Harrison DC, Pearson T, Van Remmen H, Richardson A, Brooks SV, Jackson MJ, McArdle A (2010) The age-related failure of adaptive responses to contractile activity in skeletal muscle is mimicked in young mice by deletion of Cu, Zn superoxide dismutase. Aging Cell 9:979–990

  40. Woledge RC, Curtin NA, Homsher E (1985) Energetic aspects of muscle contraction. Academic Press, Orlando

Download references


Financial support was provided by the National Institute on Aging, grant AG-020591.

Author information

Correspondence to Susan V. Brooks.

About this article

Cite this article

Larkin, L.M., Hanes, M.C., Kayupov, E. et al. Weakness of whole muscles in mice deficient in Cu, Zn superoxide dismutase is not explained by defects at the level of the contractile apparatus. AGE 35, 1173–1181 (2013).

Download citation


  • Contractility
  • Oxidative stress
  • Permeabilized fiber
  • Skeletal muscle
  • Specific force