The authors hypothesized that FK506 improves maximal muscle force (P0) recovery during early muscle reinnervation. Rat peroneal nerve was unilaterally cut and repaired. Rats received subcutaneous injections of vehicle (controls) or FK506 at 1 mg/kg (FK506-1MG) or 5 mg/kg (FK506-5MG) for 3 weeks. Extensor digitorum longus (EDL) isometric muscle P0 was measured bilaterally 4 weeks postoperatively. FK506 treatment adversely affected body mass. With body mass as a covariate, the P0 for denervated-reinnervated muscle in the FK506-5MG group was statistically significantly higher by 34 percent and 32 percent, compared with controls and FK506-1MG groups. There was no group difference for the contralateral, nerve-intact EDL muscle P0, when loss of body mass was considered. NCAM immunohistologic data showed significantly better reinnervation of the denervated muscle in a dose-dependent fashion. Thus, FK506 treatment at high dose improves early recovery of force in denervated-reinnervated muscle, following nerve repair, when loss of body mass is considered.
KEYWORDS
Tacrolimus - denervation - muscle
REFERENCES
-
1
Aird R B, Naffziger H C.
The pathology of human striated muscle following denervation.
J Neurosurg.
1953;
10
216-227
-
2
Birch R, Raji A RM.
Repair of median and ulnar nerves-primary suture is best.
J Bone Joint Surg.
1991;
73B
154-157
-
3
Bowden R EM, Gutman E.
Denervation and reinnervation of human voluntary muscle.
Brain.
1944;
67
273-310
-
4
Gordon T, Stein R B.
Reorganization of motor-unit properties in reinnervated muscles of the cat.
J Neurophysiol.
1982;
48
1175-1190
-
5
Gutmann E, Young J.
The reinnervation of muscle after various periods of atrophy.
J Anat.
1944;
78
15-43
-
6
Kobayashi J, Mackinnon S E, Watanabe O et al..
The effect of duration of muscle denervation on functional recovery in the rat model.
Muscle Nerve.
1997;
20
858-866
-
7
Schmalbruch H, Alamood W S, Lewis D M.
Morphology of long-term denervated rat soleus muscle and the effect of chronic electrical-stimulation.
J Physiol (Lond).
1991;
441
233-241
-
8
Sunderland S, Ray L J.
Denervation changes in mammalian striated muscle.
J Neurol Neurosurg Psychiatry.
1950;
13
159-177
-
9
Viguie C, Lu D X, Huang S K, Regen H, Carlson B M.
Quantitative study of the effects of long term denervation on the extensor digitorum longus muscle of the rat.
Anat Rec.
1997;
248
346-354
-
10
Ide C.
Peripheral nerve regeneration.
Neurosci Res.
1996;
25
101-121
-
11
Lundborg G, Dahlin L, Danielsen N, Zhao Q.
Trophism, tropism, and specificity in nerve regeneration.
J Reconstr Microsurg.
1994;
10
345-354
-
12
Raivich G, Kreutzberg G W.
Peripheral-nerve regeneration-role of growth factors and their receptors.
Int J Dev Neurosci.
1993;
11
311-324
-
13
Angelov D N, Neiss W F, Streppel M, Andermahr J, Mader K, Stennert E.
Nimodipine accelerates axonal sprouting after surgical repair of rat facial nerve.
J Neurosci.
1996;
16
1041-1048
-
14
Badalamente M A, Hurst L C, Stracher A.
Neuromuscular recovery using calcium protease inhibition after median nerve repair in primates.
Proc Natl Acad Sci U S A.
1989;
86
5983-5987
-
15
Campana W M, Mohiuddin L, Misasi R, O'Brien J S, Calcutt N A.
Prosaposin-derived peptides enhanced sprouting of sensory neurons in vitro and induced sprouting at motor endplates in vivo.
J Peripher Nerv Syst.
2000;
5
126-130
-
16
Gold B G, Katoh K, Storm-Dickerson T.
The immunosuppressant FK506 increases the rate of axonal regeneration in rat sciatic nerve.
J Neurosci.
1995;
15
7509-7516
-
17
Gold B G, Storm-Dickerson T, Austin D R.
The immunosuppressant FK506 increases functional recovery and neuroregeneration following peripheral nerve injury.
Restor Neurol Neurosci.
1993;
6
287-296
-
18
Lyons W E, George E B, Dawson T M, Steiner J P, Snyder S H.
Immunosuppressant FK506 promotes neurite outgrowth in cultures of PC12 cells and sensory ganglia.
Proc Natl Acad Sci USA.
1994;
91
3191-3195
-
19
Archibald S J, Wang M S, Gold B G.
FK506 accelerates axonal regeneration through an artificial nerve guide in the rat sciatic nerve transaction model.
J Peripher Nerv Syst.
1999;
4
202-210
-
20
Becker D B, Jensen J N, Myckatyn T M, Doolabh V B, Hunter D A, Mackinnon S E.
Effects of FKBP-12 ligands following tibial nerve injury in rats.
J Reconstr Microsurg.
2000;
16
613-620
-
21
Doolabh V B, Mackinnon S E.
FK506 accelerates functional recovery following nerve grafting in a rat model.
Plast Reconstr Surg.
1999;
103
1928-1936
-
22
Navarro X, Udina E, Ceballos D, Gold B G.
Effects of FK506 on nerve regeneration and reinnervation after graft or tube repair of long nerve gaps.
Muscle Nerve.
2001;
24
905-915
-
23
Wang M S, Gold B G.
FK506 increases the regeneration of spinal cord axons in a predegenerated peripheral nerve autograft.
J Spinal Cord Med.
1999;
22
287-296
-
24
Miller S W, Hassett C A, White T P, Faulkner J A.
Recovery of medial gastrocnemius muscle grafts in rats: implications for the plantar flexor group.
J Appl Physiol.
1994;
77
2773-2777
-
25 Institute of Laboratory Animals Resources .National Research Council's Guide for the Care and Use of Laboratory Animals. 7th ed. 1996 Washington, DC; National Academy Press
-
26
Urbanchek M S, Chung K C, Asato H, Washington L N, Kuzon Jr W M.
Rat walking tracks do not reflect maximal muscle force capacity.
J Reconstr Microsurg.
1999;
15
143-149
-
27
Yoshimura K, Asato H, Cederna P S, Urbanchek M G, Kuzon W M.
The effect of reinnervation on force production and power output in skeletal muscle.
J Surg Res.
1999;
81
201-208
-
28
Mendez J, Keys A.
Density and composition of mammalian muscle.
Metabolism.
1960;
9
184-188
-
29
Urbanchek M G, Picken E B, Kalliainen L K, Kuzon Jr W M.
Specific force deficit in skeletal muscles of old rats is partially explained by the existence of denervated muscle fibers.
J Gerontola Biol Sci Med Sci.
2001;
56
B191-B197
-
30
Kalliainen L K, Jejurikar S S, Liang L W, Urbanchek M G, Kuzon Jr W M.
A specific force deficit exists in skeletal muscle after partial denervation.
Muscle Nerve.
2002;
25
31-38
-
31
Sanes J R, Hall Z W.
Antibodies that bind specifically to synaptic sites on muscle fiber basal lamina.
J Cell Biol.
1979;
83
357-370
-
32
Dumont F J, Staruch M J, Koprak S L et al..
The immunosuppressive and toxic effects of FK-506 are mechanistically related: pharmacology of a novel antagonist of FK-506 and rapamycin.
J Exp Med.
1992;
176
751-760
-
33
Ellis R A, Brenner M J, Mackinnon S E, Myckatyn T M, Hunter D A.
Use of mixed lymphocyte reaction to identify subimmunosuppressive FK-506 levels in mice.
Microsurgery.
2003;
23
276-282
-
34
Nielsen F T, Leyssac P P, Kemp E, Starklint H, Dieperink H.
Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity.
Nephrol Dial Transplant.
1995;
10
334-340
-
35
Sulaiman O A, Voda J, Gold B G, Gordon T.
FK506 increases peripheral nerve regeneration after chronic axotomy but not after chronic Schwann cell denervation.
Exp Neurol.
2002;
175
127-137
-
36
Wang M S, Zeleny-Pooley M, Gold B G.
Comparative dose-dependence study of FK506 and cyclosporin A on the rate of axonal regeneration in the rat sciatic nerve.
J Pharmacol Exp Ther.
1997;
282
1084-1093
-
37
Cederna P S, Youssef M K, Asato H, Urbanchek M G, Kuzon Jr W M.
Skeletal muscle reinnervation by reduced axonal numbers results in whole muscle force deficits.
Plast Reconstr Surg.
2000;
105
2003-2009
-
38
Chunasuwankul R, Ayrout C, Dereli Z, Gal A, Lanzetta M, Owen E.
Low dose discontinued FK506 treatment enhances peripheral nerve regeneration.
Int Surg.
2002;
87
274-278
-
39
Gold B G, Stormdickerson T, Austin D R.
The immunosuppressant FK506 increases functional recovery and nerve regeneration following peripheral-nerve injury.
Restor Neurol Neurosci.
1994;
6
287-296
-
40
Grand A G, Myckatyn T M, Mackinnon S E, Hunter D A.
Axonal regeneration after cold preservation of nerve allografts and immunosuppression with tacrolimus in mice.
J Neurosurg.
2002;
96
924-932
-
41
Lee M, Doolabh V B, Mackinnon S E, Jost S.
FK506 promotes functional recovery in crushed rat sciatic nerve.
Muscle Nerve.
2000;
23
633-640
-
42
Myckatyn T M, Ellis R A, Grand A G et al..
The effects of rapamycin in murine peripheral nerve isografts and allografts.
Plast Reconstr Surg.
2002;
109
2405-2417
-
43
Sobol J B, Lowe III J B, Yang R K, Sen S K, Hunter D A, Mackinnon S E.
Effects of delaying FK506 administration on neuroregeneration in a rodent model.
J Reconstr Microsurg.
2003;
19
113-118
-
44
Weinzweig N, Grindel S, Gonzalez M, Kuy D, Fang J, Shahani B.
Peripheral-nerve allotransplantation in rats immunosuppressed with transient or long-term FK-506.
J Reconstr Microsurg.
1996;
12
451-459
-
45
Jost S C, Doolabh V B, Mackinnon S E, Lee M, Hunter D.
Acceleration of peripheral nerve regeneration following FK506 administration.
Restor Neurol Neurosci.
2000;
17
39-44
-
46
Kline D G, Hacket E R, May P R.
Evaluation of nerve injuries by evoked potentials and electromyography.
J Neurosurg.
1969;
31
128-136
-
47
Fansa H, Keilhoff G, Horn T, Altmann S, Wolf G, Schneider W.
Stimulation of Schwann cell proliferation and axonal regeneration by FK506.
Restor Neurol Neurosci.
2000;
16
77-86
-
48
Klettner A, Herdegen T.
The immunophilin-ligands, FK506 and V-10,367 mediate neuroprotection by the heat shock response.
Br J Pharmacol.
2003;
138
1004-1012
-
49
Sezen S F, Hoke A, Burnett A L, Snyder S H.
Immunophilin ligand FK506 is neuroprotective for penile innervation.
Nat Med.
2001;
7
1073-1074
-
50
Steiner J P, Connolly M A, Valentine H L et al..
Neurotrophic actions of nonimmunosuppressive analogues of immunosuppressive drugs FK506, rapamycin and cyclosporin. A.
Nat Med.
1997;
3
421-428
Melanie G UrbanchekPh.D.
University of Michigan, Section of Plastic and Reconstructive Surgery
2130 Taubman Health Care Center
1500 E. Medical Center Drive
Ann Arbor, MI 48109-0340
