Skeletal muscle growth in young rats is inhibited by chronic exposure to IL-6 but preserved by concurrent voluntary endurance exercise

Abstract

Childhood diseases are often accompanied by chronic inflammation, which is thought to negatively impact growth. Interleukin-6 (IL-6) is typically cited as an indicator of inflammation and is linked to impaired growth. This study was designed to isolate and identify potential effects of chronic IL-6 exposure on skeletal muscle growth during development. A second aim was to determine if endurance exercise, thought to antagonize chronic inflammation, would interact with any effects of IL-6. The muscles of one leg of rapidly growing rats were exposed to IL-6 or vehicle for 14 days. Subgroups of IL-6-infused rats were provided access to running wheels. Local IL-6 infusion resulted in approximately 13% muscle growth deficit (myofibrillar protein levels). Exercise (>4,000 m/day) prevented this deficit. IL-6 infusion increased mRNA for suppressor of cytokine signaling-3 (SOCS3) and tumor necrosis factor-alpha (TNF-alpha), and this was not prevented by exercise. IL-6 infusion increased the mRNAs for atrogin, insulin-like growth factor-I (IGF-I), and IGF binding protein-4 (IGFBP4), and these effects were mitigated by exercise. Exercise stimulated an increase in total RNA ( approximately 19%) only in the IL-6-infused muscle, suggesting that a compensatory increase in translational capacity was required to maintain muscle growth. This study indicates that IL-6 exposure during periods of rapid growth in young animals can retard growth possibly via interactions with key growth factors. Relatively high volumes of endurance-type exercise do not exacerbate the negative effects of IL-6 and in fact were found to be beneficial in protecting muscle growth.

Fig. 1.

Changes in body mass during 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running. #P < 0.05 vs. sham and IL-6.

Fig. 2.

Blood plasma concentrations of selected cytokines during 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running. *P < 0.05 vs. sham.

Fig. 3.

Effects of 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running on myosin heavy chain (MHC) type IIa (A) and type IIb (B) protein proportions in rat medial gastrocnemius (MG) muscles. CON, contralateral muscle; INF, IL-6-infused muscle. ¹ P < 0.05 vs. sham; ² P < 0.05 vs. sedentary IL-6 contralateral. ³ P < 0.05 vs. sedentary IL-6 infused.

Fig. 4.

Effects of 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running on IL-6 receptor mRNA levels in rat MG muscles. ¹ P < 0.05 vs. sham. ² P < 0.05 vs. sedentary IL-6 contralateral. ³ P < 0.05 vs. sedentary IL-6 infused.

Fig. 5.

Effects of 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running on mRNA levels for CIS (A) and suppressor of cytokine signaling 2 (SOCS2) (B) in rat MG muscles. ² P < 0.05 vs. sedentary IL-6 contralateral. ³ P < 0.05 vs. sedentary IL-6 infused.

Fig. 6.

Effects of 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running on MG muscle total (A) and myofibrillar (B) protein content. ¹ P < 0.05 vs. sham. ² P < 0.05 vs. sedentary IL-6 contralateral. ⁴ P < 0.05 vs. run contralateral muscle. ⁵ P < 0.05 vs. IL-6-infused run muscle.

Fig. 7.

Effects of 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running on the level of IGF-I (A) and IGF binding protein 4 (IGFBP4) (B) mRNA present in rat MG muscle. ¹ P < 0.05 vs. sham. ² P < 0.05 vs. sedentary IL-6 contralateral. ⁴ P < 0.05 vs. run contralateral muscle.

Fig. 8.

Effects of 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running on the IGF-I/insulin receptor (IGFR1) protein level present in rat MG muscle. ¹ P < 0.05 vs. sham. ² P < 0.05 vs. sedentary IL-6 contralateral.

Fig. 9.

Effects of 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running on the level of procollagen III (Col-3) mRNA present in rat MG muscle. ¹ P < 0.05 vs. sham. ² P < 0.05 vs. sedentary IL-6 contralateral. ⁴ P < 0.05 vs. run contralateral muscle.

Fig. 10.

Effects of 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running on the level of atrogin (A) and p21 (B) mRNA present in rat MG muscle. ¹ P < 0.05 vs. sham. ² P < 0.05 vs. sedentary IL-6 contralateral. ⁴ P < 0.05 vs. run contralateral muscle.

Fig. 11.

Effects of 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running on the amount of total RNA (A) and the ratio of total protein to total RNA (B) present in rat MG muscle. ¹ P < 0.05 vs. sham. ² P < 0.05 vs. sedentary IL-6 contralateral. ⁴ P < 0.05 vs. run contralateral muscle.

Fig. 12.

Effects of 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running on the level of TNF-α (A) and TNF-α receptor (B) present in rat MG muscle. ¹ P < 0.05 vs. sham. ² P < 0.05 vs. sedentary IL-6 contralateral. ⁴ P < 0.05 vs. run contralateral muscle.

Fig. 13.

Effects of 14 days of localized muscle infusion of vehicle (sham), IL-6, or IL-6 plus concurrent voluntary running on the level of SOCS3 mRNA and protein present in rat MG muscle. Representative immunoblot for SOCS3 protein (A), SOCS3 protein in densitometer units (not significant) (B), and SOCS3 mRNA (C). ¹ P < 0.05 vs. sham. ² P < 0.05 vs. sedentary IL-6 contralateral. 4 P < 0.05 vs. run contralateral muscle.