Ribosome biogenesis and degradation regulate translational capacity during muscle disuse and reloading

Abstract

Background Translational capacity (i.e. ribosomal mass) is a key determinant of protein synthesis and has been associated with skeletal muscle hypertrophy. The role of translational capacity in muscle atrophy and regrowth from disuse is largely unknown. Therefore, we investigated the effect of muscle disuse and reloading on translational capacity in middle‐aged men (Study 1) and in rats (Study 2). Methods In Study 1, 28 male participants (age 50.03 ± 3.54 years) underwent 2 weeks of knee immobilization followed by 2 weeks of ambulatory recovery and a further 2 weeks of resistance training. Muscle biopsies were obtained for measurement of total RNA and pre‐ribosomal (r)RNA expression, and vastus lateralis cross‐sectional area (CSA) was determined via peripheral quantitative computed tomography. In Study 2, male rats underwent hindlimb suspension (HS) for either 24 h (HS 24 h, n = 4) or 7 days (HS 7d, n = 5), HS for 7 days followed by 7 days of reloading (Rel, n = 5) or remained as ambulatory weight bearing (WB, n = 5) controls. Rats received deuterium oxide throughout the study to determine RNA synthesis and degradation, and mTORC1 signalling pathway was assessed. Results Two weeks of immobilization reduced total RNA concentration (20%) and CSA (4%) in men (both P ≤ 0.05). Ambulatory recovery restored total RNA concentration to baseline levels and partially restored muscle CSA. Total RNA concentration and 47S pre‐rRNA expression increased above basal levels after resistance training (P ≤ 0.05). In rats, RNA synthesis was 30% lower while degradation was ~400% higher in HS 7d in soleus and plantaris muscles compared with WB (P ≤ 0.05). mTORC1 signalling was lower in HS compared with WB as was 47S pre‐rRNA (P ≤ 0.05). With reloading, the aforementioned parameters were restored to WB levels while RNA degradation was suppressed (P ≤ 0.05). Conclusions Changes in RNA concentration following muscle disuse and reloading were associated with changes in ribosome biogenesis and degradation, indicating that both processes are important determinants of translational capacity. The pre‐clinical data help explain the reduced translational capacity after muscle immobilization in humans and demonstrate that ribosome biogenesis and degradation might be valuable therapeutic targets to maintain muscle mass during disuse.

Determining the contributions of protein synthesis and breakdown to muscle atrophy requires non‐steady‐state equations

“…Changes in ribosomal synthesis (ribosomal biogenesis) have been shown to correlate with changes in muscle protein synthesis during loading 15,16,34 . In recent studies, we have shown that atrophy caused by disuse is associated with decreases in myofibrillar protein synthesis, increases in myofibrillar protein degradation and dramatically upregulated ribosomal degradation without changes to ribosome biogenesis 16,33 . In the current investigation, we observe that a correlation between ribosome biogenesis and myofibrillar protein synthesis exists in the sham limb (during normal loading conditions), but not in the denervated limb.…”

“…The decline in translational efficiency and capacity caused by a period of muscle disuse may be a therapeutic target to regain muscle in the period after disuse 33 . Changes in ribosomal synthesis (ribosomal biogenesis) have been shown to correlate with changes in muscle protein synthesis during loading 15,16,34 .…”

Physiological Reloading Recovers Histologically Disuse Atrophy of the Articular Cartilage and Bone by Hindlimb Suspension in Rat Knee Joint

“…In the skeletal muscle, it is widely known that inactivity causes disuse atrophy 21-23 and that reactivation improves atrophy. 24-26 In contrast, there are no previous studies on its treatment and recovery, and the treatment and recovery processes for disuse atrophy of the articular cartilage are unclear. Owing to the absence of blood vessels and dependence on nutrition from the synovial fluid, it is traditionally believed that the articular cartilage has a poor repair capacity.…”

Choline acts during preimplantation development of the bovine embryo to program postnatal growth and alter muscle DNA methylation

“…Ribosomes are central to conversion of mRNA to protein 41 and an increase in mRNA coding for ribosomal RNAs have been observed during hypertrophy of rat cardiomyocytes, 42 plantaris muscle in rat and vastus lateralis in human. 43 Reduction in methylation of genomic regions of ribosomal DNA is associated with increased biogenesis of ribosomal RNA. 44 Furthermore, many of the genes associated with DMC are associated with growth or muscle function.…”

“…The predominant change in methylation for these genes due to choline was hypomethylation. Ribosomes are central to conversion of mRNA to protein 41 and an increase in mRNA coding for ribosomal RNAs have been observed during hypertrophy of rat cardiomyocytes, 42 plantaris muscle in rat and vastus lateralis in human 43 . Reduction in methylation of genomic regions of ribosomal DNA is associated with increased biogenesis of ribosomal RNA 44 .…”