Cachectic effect of ciliary neurotrophic factor on innervated skeletal muscle

Abstract

Recombinant human ciliary neurotrophic factor (rh-CNTF) was reported to attenuate skeletal muscle wasting in rats after unilateral transection of the sciatic nerve (M. E. Helgren, S. P. Squinto, H. L. Davis, D. J. Parry, T. G. Bolton, C. S. Heck, Y. Zhu, G. D. Yancopoulos, R. M. Lindsay, and P. S. DiStefano. Cell 76: 493-504, 1994). Under the experimental conditions reported herein, the absolute masses of the denervated gastrocnemius and soleus muscles were not increased in mature or immature rats of either sex by treatment with rhCNTF. At the highest doses of rhCNTF (1 and 0.1 mg/kg), increases in the ratio of the masses of the denervated to the contralateral innervated gastrocnemius and soleus muscles could be attributed entirely to a muscle-wasting effect on the contralateral innervated muscle rather than any muscle-sparing effect on the denervated muscle. The muscle-wasting effects of rhCNTF were associated with reductions in body weight gain and reduced food intake. Pair-fed rats lost less body weight and skeletal muscle mass than rhCNTF-injected freely fed rats but experienced significantly greater loss of visceral mass. Male rats displayed greater loss of body weight and skeletal muscle mass than female rats. Recombinant inhibitors of the cachectic cytokines, tumor necrosis factor and interleukin-1, did not significantly alter the wasting effects of rhCNTF. These findings demonstrate that, in contrast to its well-characterized trophic effects on cells of the nervous system, rhCNTF causes atrophy of skeletal muscle by mechanisms involving both anorexia and cachexia based on the results of pair-feeding experiments.

Ciliary neurotrophic factor activates leptin-like pathways and reduces body fat, without cachexia or rebound weight gain, even in leptin-resistant obesity

“…These findings stand in contrast to previous data suggesting a cachectic action of CNTF (16,21,22). However, it should be noted that much higher doses of CNTF were used in those studies.…”

Development of the Vertebrate Neuromuscular Junction

“…Unfortunately, interpretation of these experiments is made complicated by relatively nonspecific effects of such treatments. For example, CNTF exerts a cachectic effect on skeletal muscle that may delay maturation (D Martin et al 1996), and several of the factors cause axonal sprouting (Gurney et al 1992;Kwon & Gurney 1994;Caroni et al 1994). Thus, the idea that there is a retrogradely diffusing synaptotrophic molecule at the NMJ is attractive but unproven.…”

Effects of testosterone on the development of a sexually dimorphic neuromuscular system in ciliary neurotrophic factor receptor knockout mice

“…Finally, CNTFR␣ protein levels are upregulated in skeletal muscles of aged rats, and localized administration of CNTF reverses the age-related decline in muscle strength (Guillet et al, 1999). In contrast to these myotrophic effects of CNTF seen after injury or in aging, however, CNTF may actually promote the catabolism of normal, innervated muscle in nonaged adults (Henderson et al, 1994;Martin et al, 1996). The model proposed above for the role of CNTFR␣ in perineal muscle development is therefore consistent with findings in adults: CNTF receptors on muscle appear to play an important myogenic role during times of muscle challenge, such as after denervation, during age-related declines in muscle function, or during androgen deprivation of androgendependent muscles.…”