Potential Role of MicroRNA in the Anabolic Capacity of Skeletal Muscle With Aging

Abstract

Age-induced loss of skeletal muscle mass and function, termed sarcopenia, may be the result of diminished response to anabolic stimulation. This review will explore the hypothesis that alterations in the expression of microRNA with aging contributes to reduced muscle plasticity resulting in impaired skeletal muscle adaptations to exercise-induced anabolic stimulation.

Figure 1

microRNA Biogenesis; Biogenesis of miRNA begins in the nucleus of the cell where RNA polymerase II transcribes primary-miRNA (pri-miRNA), consisting of thousands of nucleotides with stem-loop structures. The enzyme Drosha, a member of the ribonuclease (RNase) III superfamily of double-stranded RNA-specific endoribonuclease, together with DiGeorge syndrome critical region gene (DGCR8), cleaves the stem-loop structure of the pri-miRNA to form precursor miRNA (pre-miRNA). Conversion of pri-miRNA to pre-miRNA is a critical step, as it is site-specific, dictating the sequence of the mature miRNA. The pre-miRNA translocates out of the nucleus into the cytoplasm by small RNA transporter Exportin 5, which is a GTP dependent process. Once in the cytoplasm, pre-miRNA is processed by Dicer, another enzyme in the RNase III family, to form mature miRNA. One strand of the mature miRNA is bound by Argonaute, a protein that directly binds to miRNA, forming a protein complex called RNA-induced silencing complex (RISC), allowing miRNA to bind to target mRNA, resulting in post-transcriptional modifications that repress the translation of protein

Figure 2

Schematic of hypothesized feed forward mechanism of elevated muscle protein synthesis (MPS) rates modulation microRNA expression to aid in regulation of training adaptions.

Figure 3

Interaction between microRNA and intracellular signaling pathways regulating skeletal muscle protein synthesis and breakdown. Activation of mTORC1 triggers downstream signaling through p70 ribosomal S6 kinase (p70 S6K), ribosomal protein S6 (rpS6), eukaryotic elongation factor 2 kinase (eEF2), and eukaryotic initiation factor 4E-binding protein (4E-BP1), increasing mRNA translational efficiency and muscle protein synthesis. Muscle protein breakdown from ubiquitination results through the muscle-specific E3 class of ubiquitin ligases, atrogin-1/muscle atrophy F-box (MAFbx), and muscle RING finger-1 (MuRF1). Activity of atrogin-1/MAFbx and MuRF1 are regulated by the forkhead box O (FOXO) family of transcription factors, which when dephosphorylated translocate to the nucleus to mediate increased expression of these ubiquitin ligases. The ubiquinated proteins are transferred to the 26S proteasome for subsequent degradation.