Activation of the dopamine 1 and dopamine 5 receptors increase skeletal muscle mass and force production under non-atrophying and atrophying conditions.
BACKGROUND
Control of skeletal muscle mass and force production is a complex physiological process involving numerous regulatory systems. Agents that increase skeletal muscle cAMP levels have been shown to modulate skeletal muscle mass and force production. The dopamine 1 receptor and its closely related homolog, the dopamine 5 receptor, are G-protein coupled receptors that are expressed in skeletal muscle and increase cAMP levels when activated. Thus we hypothesize that activation of the dopamine 1 and/or 5 receptor will increase skeletal muscle cAMP levels thereby modulating skeletal muscle mass and force production.


METHODS
We treated isolated mouse tibialis anterior (TA) and medial gastrocnemius (MG) muscles in tissue bath with the selective dopamine 1 receptor and dopamine 5 receptor agonist SKF 81297 to determine if activation of skeletal muscle dopamine 1 and dopamine 5 receptors will increase cAMP. We dosed wild-type mice, dopamine 1 receptor knockout mice and dopamine 5 receptor knockout mice undergoing casting-induced disuse atrophy with SKF 81297 to determine if activation of the dopamine 1 and dopamine 5 receptors results in hypertrophy of non-atrophying skeletal muscle and preservation of atrophying skeletal muscle mass and force production.


RESULTS
In tissue bath, isolated mouse TA and MG muscles responded to SKF 81297 treatment with increased cAMP levels. Treating wild-type mice with SKF 81297 reduced casting-induced TA and MG muscle mass loss in addition to increasing the mass of non-atrophying TA and MG muscles. In dopamine 1 receptor knockout mice, extensor digitorum longus (EDL) and soleus muscle mass and force was not preserved during casting with SKF 81297 treatment, in contrast to significant preservation of casted wild-type mouse EDL and soleus mass and EDL force with SKF 81297 treatment. Dosing dopamine 5 receptor knockout mice with SKF 81297 did not significantly preserve EDL and soleus muscle mass and force although wild-type mouse EDL mass and force was significantly preserved SKF 81297 treatment.


CONCLUSIONS
These data demonstrate for the first time that treatment with a dopamine 1/5 receptor agonist results in (1) significant preservation of EDL, TA, MG and soleus muscle mass and EDL muscle force production during periods of atrophy and (2) hypertrophy of TA and MG muscle. These effects appear to be mainly mediated by both the dopamine 1 and dopamine 5 receptors.
Research Division, Procter & Gamble, Mason, OH, USA.
Deborah L
DL
Reichart
Richard T
RT
Hinkle
Frank R
FR
Lefever
Elizabeth T
ET
Dolan
Jeffrey A
JA
Dietrich
David R
DR
Sibley
Robert J
RJ
Isfort
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009133:Muscular Atrophy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*; D050641:Receptors, Dopamine D5 / Q000819:agonists / Q000172:deficiency / Q000378:metabolism*
D001552:Benzazepines; D018491:Dopamine Agonists; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; C067113:SK&F 81297
Ann Intern Med. 1998 Jul 1;129(1):18-26
9652995
J Neurosci. 1995 Dec;15(12):7821-36
8613722
J Biol Chem. 1995 Jun 16;270(24):14672-8
7782330
Ann Surg. 1999 Feb;229(2):298-302
10024114
Mol Pharmacol. 1995 Dec;48(6):988-94
8848015
J Appl Physiol (1985). 2005 Feb;98(2):655-62
15649881
Heart Lung. 2007 Jan-Feb;36(1):58-63
17234478
Brain Res Mol Brain Res. 1992 Oct;15(3-4):181-8
1331674
Eur Heart J. 1997 Feb;18(2):259-69
9043843
J Biol Chem. 1996 Aug 9;271(32):19503-8
8702641
J Pharmacol Exp Ther. 1994 Jan;268(1):495-502
8301592
Nature. 1991 Apr 18;350(6319):614-9
1826762
Physiol Rev. 1998 Jan;78(1):189-225
9457173
Am J Respir Crit Care Med. 1998 Aug;158(2):629-34
9700144
J Appl Physiol (1985). 1990 Jan;68(1):1-12
2179205
Curr Opin Clin Nutr Metab Care. 1999 May;2(3):201-5
10456248
Sports Med. 1990 Jul;10(1):42-58
2197699
Trends Pharmacol Sci. 1994 Jul;15(7):264-70
7940991
Mol Pharmacol. 2009 Apr;75(4):843-54
19171671
Annu Rev Pharmacol Toxicol. 1993;33:281-307
8494342
J Neurol Sci. 1999 Jan 1;162(1):38-50
10064167
Pharmacol Ther. 1994;64(2):291-370
7878079
Muscle Nerve. 2002 May;25(5):729-734
11994968
Science. 1976 Apr 30;192(4238):471-3
176728
J Recept Signal Transduct Res. 1995 Jan-Mar;15(1-4):267-81
8903944
Annu Rev Neurosci. 1993;16:299-321
8460895
Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E889-98
12959937
Exp Physiol. 2006 Jul;91(4):731-40
16644796
Ann Surg. 1999 May;229(5):713-20; discussion 720-2
10235530
Mov Disord. 1988;3(2):117-25
3221899
J Appl Physiol (1985). 2004 Dec;97(6):2339-46
15258132
Curr Opin Pharmacol. 2010 Feb;10(1):93-9
19897420
J Biol Chem. 2004 Aug 20;279(34):35671-8
15159403
Biol Res Nurs. 2002 Jan;3(3):140-9
12003442
Clin Sci (Lond). 1998 Apr;94(4):413-23
9640347
Muscle Nerve. 2005 Dec;32(6):775-81
16116651
Biochem J. 1987 Jan 1;241(1):153-9
3566707
Eur Heart J. 1997 Dec;18(12):1865-72
9447313
Proc Natl Acad Sci U S A. 1990 Sep;87(17):6723-7
2168556
Clin Sci (Lond). 1993 Jun;84(6):651-4
8334811
J Neurochem. 1991 Oct;57(4):1445-51
1832710
J Neurochem. 1993 Mar;60(3):804-16
8436971
Arch Phys Med Rehabil. 1997 Jan;78(1):13-8
9014951
Naunyn Schmiedebergs Arch Pharmacol. 1977 Dec;301(2):109-13
23500
Trends Pharmacol Sci. 1995 Aug;16(8):270-5
7482988