Brain Advance Access originally published online on August 20, 2009
Brain 2009 132(10):2724-2733; doi:10.1093/brain/awp208
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Expression of neurotrophic factors in diabetic muscle—relation to neuropathy and muscle strength
1 Clinical Neurology Research Group, Department of Neurology, Aarhus University Hospital, Denmark 2 The Medical Research Laboratories, Clinical Institute and Medical Department M (Diabetes and Endocrinology), Aarhus University Hospital, Denmark
Correspondence to: Christer Swan Andreassen, Clinical Neurology Research Group, Department of Neurology, Noerrebrogade 44, Aarhus University Hospital, 8000 Aarhus C., Denmark E-mail: christer.andreassen{at}ki.au.dk
Diabetic polyneuropathy can lead to atrophy and weakness of distally located striated muscles due to denervation. Lack of neurotrophic support is believed to contribute to the development of diabetic neuropathy. In this study, we measured the expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), neurotrophin 4 (NT-4) and ciliary neurotrophic factor (CNTF) in muscle biopsies taken from the gastrocnemic and deltoid muscles in 42 diabetic patients and 20 healthy control subjects. To express the distal neuropathic gradient and to reduce interindividual variation, a distal/proximal ratio between expression levels in the gastrocnemic and deltoid muscles was calculated for all neurotrophic factors. Neuropathic status was determined by clinical examination, electrophysiological studies and quantitative sensory examination in diabetic patients, and muscle strength at both the shoulder and ankle was assessed by isokinetic dynamometry. Distal/proximal ratios for NT-3 were lower in diabetic patients [median (range) 110.7 (39.8–546.8)] than in controls [157.6 (63.3–385.4); (P < 0.05)], and in neuropathic diabetic patients [107.1 (39.8–326.0)] versus patients without neuropathy [134.5 (46.6–546.8); (P < 0.005)]. Further, ratios for NT-3 were related to muscle strength (rs = 0.41, P < 0.01) and showed a tendency towards a negative relationship to the combined score of all measures of neuropathy [Neuropathy rank-sum score (NRSS)] (rs = –0.27, P = 0.09). Similar trends were observed for ratios for NT-4. Ratios for NGF (rs = –0.32, P < 0.05) and BDNF (rs = –0.32, P < 0.05) were related to NRSS, but not to muscle strength. Ratios for CNTF were higher in diabetic patients [64.6 (23.7–258.7)] compared with controls [50.2 (27.2–186.4); (P < 0.05)], but showed no relationship to neither NRSS nor muscle strength. Our results show that the expression of NT-3 is reduced in striated muscles in diabetic patients and is related to muscle weakness and neuropathy. We suggest that lack of NT-3 contributes to insufficient re-innervation leading to the loss of muscle strength in diabetic neuropathy.
Key Words: diabetic polyneuropathy; neurotrophic factor; striated muscle; muscle strength; human
Abbreviations: BDNF, brain-derived neurotrophic factor; CNTF, ciliary neurotrophic factor; CMAP, compound motor action potential; CV, coefficient of variation; DPN, diabetic polyneuropathy; ISH, in situ hybridization; NGF, nerve growth factor; NIS, neuropathy impairment score; NRSS, neuropathy rank-sum score; NSS, neurological symptom score; NT-3, neurotrophin 3; NT-4, neurotrophin 4; PCR, polymerase chain reaction; PNS, peripheral nervous system; UACR, u-albumin/creatinine ratio; VPF, vibratory perception thresholds
Received May 5, 2009. Revised June 19, 2009. Accepted June 25, 2009.