title: Effects of N-acetylcysteine on isolated mouse skeletal muscle: contractile properties, temperature dependence, and metabolism.
abstract: The effects of the general antioxidant N-acetylcysteine (NAC) on muscle function and metabolism were examined. Isolated paired mouse extensor digitorum longus muscles were studied in the absence or presence of 20 mM NAC. Muscles were electrically stimulated to perform 100 isometric tetanic contractions (300 ms duration) at frequencies resulting in ∼85% of maximal force (70-150 Hz at 25-40 °C). NAC did not significantly affect peak force in the unfatigued state at any temperature but significantly slowed tetanic force development in a temperature-dependent fashion (e.g., time to 50% of peak tension averaged 35 ± 2 ms [control] and 37 ± 1 ms [NAC] at 25 °C vs. 21 ± 1 ms [control] and 52 ± 6 ms [NAC, P < 0.01] at 40 °C). During repeated contractions, NAC maximally enhanced peak force by the fifth tetanus at all temperatures (by ∼30%). Thereafter, the effect of NAC disappeared rapidly at high temperatures (35-40 °C) and more slowly at the lower temperatures (25-30 °C). At all temperatures, the enhancing effect of NAC on peak force was associated with a slowing of relaxation. NAC did not significantly affect myosin light chain phosphorylation at rest or after five contractions (∼50% increase vs. rest). After five tetani, lactate and inorganic phosphate increased about 20-fold and 2-fold, respectively, both in control and NAC-treated muscles. Interestingly, after five tetani, the increase in glucose 6-P was ∼2-fold greater, whereas the increase in malate was inhibited by ∼75% with NAC vs. control, illustrating the metabolic effects of NAC. NAC slightly decreased the maximum shortening velocity in early fatigue (five to seven repeated tetani). These data demonstrate that the antioxidant NAC transiently enhances muscle force generation by a mechanism that is independent of changes in myosin light chain phosphorylation and inorganic phosphate. The slowing of relaxation suggests that NAC enhances isometric force by facilitating fusion (i.e., delaying force decline between pulses). The initial slowing of tension development and subsequent slowing of relaxation suggest that NAC would result in impaired performance during a high-intensity dynamic exercise.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 17177, Stockholm, Sweden, abram.katz@ki.se.
authors.forename: Abram
authors.initials: A
authors.lastname: Katz
authors.forename: Andrés
authors.initials: A
authors.lastname: Hernández
authors.forename: Diana Marcela Ramos
authors.initials: DM
authors.lastname: Caballero
authors.forename: Javier Fernando Bonilla
authors.initials: JF
authors.lastname: Briceno
authors.forename: Laura Victoria Rivera
authors.initials: LV
authors.lastname: Amezquita
authors.forename: Natalia
authors.initials: N
authors.lastname: Kosterina
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Bruton
authors.forename: Håkan
authors.initials: H
authors.lastname: Westerblad
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D005260:Female; D006358:Hot Temperature; D007537:Isometric Contraction; D019344:Lactic Acid / Q000378:metabolism; D008293:Malates / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009126:Muscle Relaxation; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018994:Myosin Light Chains / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D010766:Phosphorylation
chemical_list: D000975:Antioxidants; D008293:Malates; D018994:Myosin Light Chains; D010710:Phosphates; D019344:Lactic Acid; C030298:malic acid; D000111:Acetylcysteine
references.citation: Am J Physiol Cell Physiol. 2007 Apr;292(4):C1353-60
references.pmid: 17122413
references.citation: J Physiol. 2011 Apr 1;589(Pt 7):1791-801
references.pmid: 21486840
references.citation: J Physiol. 2008 Jan 1;586(1):175-84
references.pmid: 18006575
references.citation: J Physiol. 2008 Apr 1;586(7):2003-14
references.pmid: 18258657
references.citation: J Appl Physiol (1985). 2010 Apr;108(4):950-61
references.pmid: 20093666
references.citation: J Biol Chem. 2004 Aug 13;279(33):34682-90
references.pmid: 15178689
references.citation: J Physiol. 1993 Aug;468:729-40
references.pmid: 8254532
references.citation: Antioxid Redox Signal. 2013 Feb 20;18(6):603-21
references.pmid: 23050834
references.citation: J Biomech. 2007;40(14):3121-9
references.pmid: 17499255
references.citation: Physiol Rev. 2000 Apr;80(2):853-924
references.pmid: 10747208
references.citation: J Physiol. 2011 May 1;589(Pt 9):2119-27
references.pmid: 21041533
references.citation: J Physiol. 1978 Oct;283:501-21
references.pmid: 722588
references.citation: J Appl Physiol (1985). 2004 Oct;97(4):1477-85
references.pmid: 15194675
references.citation: J Physiol. 2006 Aug 15;575(Pt 1):251-62
references.pmid: 16777943
references.citation: Muscle Nerve. 2005 Nov;32(5):633-8
references.pmid: 16025522
references.citation: J Pharmacol Exp Ther. 2011 Aug;338(2):711-7
references.pmid: 21606175
references.citation: Am J Physiol. 1992 Apr;262(4 Pt 1):C975-9
references.pmid: 1566823
references.citation: J Physiol. 2005 Apr 1;564(Pt 1):189-99
references.pmid: 15718257
references.citation: Respir Physiol Neurobiol. 2006 Apr 28;151(2-3):229-41
references.pmid: 16481226
references.citation: J Appl Physiol (1985). 1994 Jul;77(1):317-24
references.pmid: 7961253
references.citation: Physiol Rev. 2008 Oct;88(4):1243-76
references.pmid: 18923182
references.citation: Am J Physiol. 1991 Jun;260(6 Pt 1):E859-64
references.pmid: 2058662
references.citation: J Appl Physiol (1985). 1997 Apr;82(4):1119-25
references.pmid: 9104848
references.citation: AAPS J. 2006 Aug 18;8(3):E521-31
references.pmid: 17025271
references.citation: Arch Biochem Biophys. 2011 Jun 15;510(2):120-8
references.pmid: 21284933
references.citation: PLoS One. 2010 Dec 20;5(12):e15354
references.pmid: 21187957
references.citation: J Gen Physiol. 1997 Mar;109(3):385-99
references.pmid: 9089444
references.citation: Free Radic Biol Med. 2008 Jan 15;44(2):169-79
references.pmid: 18191753
references.citation: J Appl Physiol (1985). 1994 Nov;77(5):2434-9
references.pmid: 7868466
references.citation: Am J Physiol Cell Physiol. 2006 Jul;291(1):C147-54
references.pmid: 16481370
references.citation: J Physiol. 2012 Mar 15;590(6):1443-63
references.pmid: 22250211
references.citation: Am J Physiol Cell Physiol. 2007 Aug;293(2):C650-60
references.pmid: 17459949
references.citation: Free Radic Biol Med. 2011 Jul 15;51(2):327-36
references.pmid: 21619928
references.citation: Acta Physiol (Oxf). 2008 Mar;192(3):413-20
references.pmid: 17973952
references.citation: FASEB J. 2001 Feb;15(2):309-11
references.pmid: 11156946
references.citation: Antioxid Redox Signal. 2011 Nov 1;15(9):2487-99
references.pmid: 21375476
references.citation: Am J Respir Crit Care Med. 1997 Nov;156(5):1567-71
references.pmid: 9372677
references.citation: J Appl Physiol (1985). 1990 May;68(5):2107-13
references.pmid: 2361912
references.citation: Free Radic Res. 2008 Apr;42(4):372-7
references.pmid: 18404536
references.citation: J Physiol. 2008 Jan 1;586(1):197-210
references.pmid: 17974587
references.citation: Am J Respir Crit Care Med. 2004 May 1;169(9):1022-7
references.pmid: 15001462
references.citation: J Appl Physiol (1985). 2007 Apr;102(4):1671-6
references.pmid: 17082366
references.citation: J Clin Invest. 1994 Dec;94(6):2468-74
references.pmid: 7989604
references.citation: Am J Physiol. 1987 Jun;252(6 Pt 1):C630-9
references.pmid: 3591933
references.citation: J Appl Physiol (1985). 2003 Apr;94(4):1572-82
references.pmid: 12496140
references.citation: Biochim Biophys Acta. 2009 Dec;1792(12):1185-93
references.pmid: 19786098