Administration of insulin‐like growth factor‐I improves fatigue resistance of skeletal muscles from dystrophic mdx mice

Abstract

Muscle fatigue occurs in many neuromuscular diseases, including the muscular dystrophies, and it contributes to a loss of functional capacity and reduced quality of life for affected patients. An improvement in fatigue resistance has been observed in diaphragm muscles of mdx mice following insulin-like growth factor-I (IGF-I) administration. Whether similar treatment can improve locomotor muscle function in mdx mice is not known. We examined the efficacy of IGF-I administration (1 mg/kg daily s.c. for 8 weeks) on structural, metabolic, and functional properties of extensor digitorum longus (EDL) and soleus muscles of mdx mice, and tested the hypothesis that IGF-I treatment would improve function in these muscles. After treatment, muscles were more resistant to fatigue during repeated maximal contractions than muscles from untreated mice, an improvement associated with increased muscle fiber succinate dehydrogenase activity in the absence of changes in cellular (single-fiber) contractile activation characteristics. The findings have important clinical implications, not just for the dystrophinopathies, but for all neuromuscular pathologies where fatigue of locomotor muscles limits functional capacity and decreases quality of life.

Comparative evaluation of IGF-I gene transfer and IGF-I protein administration for enhancing skeletal muscle regeneration after injury

“…We have demonstrated similar effects in previous studies, where recombinant IGF-I protein was delivered to mice at an identical dose via mini-osmotic pumps. 28,29 In these studies, systemic IGF-I protein administration induced morphological and functional changes, but IGF-I levels, as measured by RIA, were elevated in blood serum, but not in diaphragm or limb muscles. 28,29 Given its therapeutic potential to enhance restoration of muscle structure and function after damage, closer examination of the mechanisms of action of IGF-I at this dose and route of delivery is warranted.…”

“…28,29 In these studies, systemic IGF-I protein administration induced morphological and functional changes, but IGF-I levels, as measured by RIA, were elevated in blood serum, but not in diaphragm or limb muscles. 28,29 Given its therapeutic potential to enhance restoration of muscle structure and function after damage, closer examination of the mechanisms of action of IGF-I at this dose and route of delivery is warranted. It should be noted that the hastened functional recovery after electrotransfer could be directly related to higher IGF-I levels in regenerating muscle.…”

“…The other experimental group was administered recombinant IGF-I protein (IM050, GroPep, Adelaide, Australia, B1.5 mg/kg/day, subcutaneously) systemically via a mini-osmotic pump (model 1002; Alzet, Cupertino, CA, USA) implanted 4 days after notexin-induced injury, as described in detail previously. 28,29 At the completion of the treatment period, the osmotic pumps were aspirated to ensure that fouling had not occurred, and that the contents had been administered accordingly, as described previously. 28,29 The third group of mice served as controls, and received a single injection of non-coding plasmid DNA (pcDNA3.1) coupled with electrotransfer in the injured TA 4 days after notexin-induced damage.…”

“…28,29 At the completion of the treatment period, the osmotic pumps were aspirated to ensure that fouling had not occurred, and that the contents had been administered accordingly, as described previously. 28,29 The third group of mice served as controls, and received a single injection of non-coding plasmid DNA (pcDNA3.1) coupled with electrotransfer in the injured TA 4 days after notexin-induced damage.…”

Developmental programming of skeletal muscle phenotype/metabolism

“…A number of studies have implicated various growth-and transcription-factors in the regulation of oxidative metabolism and the oxidative fibre types (Chin et al, 1998;Hughes et al, 1999;Luquet et al, 2003;Gregorevic et al, 2004;Khorram et al, 2007), some of which are shown to be influenced by nutritional status. Altered organ or organ system structure during organogenesis could permanently affect an organism's metabolism.…”