Biology Reference
In-Depth Information
and motor target organs, skeletal muscles represent the most important ones
in terms of clinical relevance. The normal structural and functional integrity
of skeletal muscle depends on intact innervation, normal transmission of
impulses across the myoneural junction, and normal metabolic processes
within the muscle cell. Injury to peripheral nerves always results in imme-
diate loss of muscle function and progressive skeletal muscle atrophy, thus
representing an important cause of poor clinical results after nerve recon-
struction. Following a peripheral nerve injury, the longer the interval
between denervation and reinnervation, the poorer the degree of motor
recovery; thus, the regenerative outcome may be very poor when rein-
nervation of denervated target organs is delayed due either to a long distance
between target and lesion site or to delayed nerve repair following major
trauma (
Birch & Raji, 1991; Merle, Bour, Foucher, & Saint Laurent,
1986
). Since axons usually regrow at an average rate of 1 mm/day
(
Buchthal & Kuhl, 1979; Seddon & Fynn, 1972
), it would take a long time
for the muscle to be reinnervated. The success of reinnervation depends
therefore both on the ability of the neuron to reprogram its growth and
to establish new connections, and on the ability of muscle fibers to survive
in the absence of trophic and regulating signals derived from the nerve.
Denervated muscles come across structural, biochemical, and physiolog-
ical changes eventually leading to atrophy and apoptosis, losing up to 80% of
their mass (
Gutmann, 1962
). Over time, denervated muscles lose receptive-
ness to regenerated motor axons that reach the muscle because of a signif-
icant loss of viable muscle cells due to fiber necrosis, connective tissue
hyperplasia, and exhaustion of satellite cell regeneration (
Fu & Gordon,
1995; Irintchev, Draguhn, & Wernig, 1990; Schmalbruch, al-Amood, &
Lewis, 1991; Veltri, Kwiecien, Minet, Fahnestock, & Bain, 2005
). The loss
of neural input, including neurotransmitters, neurotrophic factors, and other
signals, promotes muscle fiber atrophy and thus reduces receptivity to
regenerated axons (
Veltri et al., 2005
). Moreover, in response to an injury,
satellite cells undergo a period of rapid proliferation; the majority of the sat-
ellite cells differentiate and fuse to form new myofibers or to repair the dam-
aged ones (
Lu, Huang, &Carlson, 1997; Schultz, Jaryszak, &Valliere, 1985
).
During early stages, denervated muscle shows also a wide spectrum of
molecular and cellular changes, including changes in gene expression. Upon
denervation, there is the upregulation of NGF, BDNF (
Zhao, Veltri, Li,
Bain, & Fahnestock, 2004
), IGF (
Tang, Cheung, Ip, & Ip, 2000
), fibroblast
growth factor (FGF), hepatocyte growth factor (
Yamaguchi, Ishii, Morita,
Oota, & Takeda, 2004
), and the alpha component of ciliary neurotrophic
