Abstract
The effects of long-term physical inactivity on the expression of microRNAs involved in the regulation of skeletal muscle mass in humans are largely unknown. MicroRNAs are short, noncoding RNAs that fine-tune target expression through mRNA degradation or by inhibiting protein translation. Intronic to the slow, type I, muscle fiber type genes MYH7 and MYH7b, microRNA-208b and microRNA-499-5p are thought to fine-tune the expression of genes important for muscle growth, such as myostatin. Spinal cord injured humans are characterized by both skeletal muscle atrophy and transformation toward fast-twitch, type II fibers. We determined the expression of microRNA-208b, microRNA-499-5p, and myostatin in human skeletal muscle after complete cervical spinal cord injury. We also determined whether these microRNAs altered myostatin expression in rodent skeletal muscle. A progressive decline in skeletal muscle microRNA-208b and microRNA-499-5p expression occurred in humans during the first year after spinal cord injury and with long-standing spinal cord injury. Expression of myostatin was inversely correlated with microRNA-208b and microRNA-499-5p in human skeletal muscle after spinal cord injury. Overexpression of microRNA-208b in intact mouse skeletal muscle decreased myostatin expression, whereas microRNA-499-5p was without effect. In conclusion, we provide evidence for an inverse relationship between expression of microRNA-208b and its previously validated target myostatin in humans with severe skeletal muscle atrophy. Moreover, we provide direct evidence that microRNA-208b overexpression decreases myostatin gene expression in intact rodent muscle. Our results implicate that microRNA-208b modulates myostatin expression and this may play a role in the regulation of skeletal muscle mass following spinal cord injury.
Highlights
Skeletal muscle has a remarkable capacity to adapt to increased physical activity and exercise training
MYH7b expression was decreased 80% at month 12 after injury, whereas in individuals with longstanding injury, expression level was 3% of that observed in the able-bodied control group (P < 0.001, Fig. 1B)
In individuals with long-standing injury, microRNA-208b expression declined to 3% of that observed in the able-bodied control group (P < 0.001), with expression levels being close to the limit of detection
Summary
Skeletal muscle has a remarkable capacity to adapt to increased physical activity and exercise training. Skeletal muscle fiber type transformation toward fast-twitch, type II, fibers occurs within the first year after complete cervical spinal cord injury (Kostovski et al 2013). Such changes reflect a more glycolytic phenotype (Aksnes et al 1996; Hjeltnes et al 1997, 1998; Talmadge 2000; Kramer et al 2006; Long et al 2011; Verdijk et al 2012), the molecular mechanism for these changes in spinal cord injured persons is incompletely described
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