Smad2/3 Proteins Are Required for Immobilization-induced Skeletal Muscle Atrophy

Abstract

Skeletal muscle atrophy promotes muscle weakness, limiting activities of daily living. However, mechanisms underlying atrophy remain unclear. Here, we show that skeletal muscle immobilization elevates Smad2/3 protein but not mRNA levels in muscle, promoting atrophy. Furthermore, we demonstrate that myostatin, which negatively regulates muscle hypertrophy, is dispensable for denervation-induced muscle atrophy and Smad2/3 protein accumulation. Moreover, muscle-specific Smad2/3-deficient mice exhibited significant resistance to denervation-induced muscle atrophy. In addition, expression of the atrogenes Atrogin-1 and MuRF1, which underlie muscle atrophy, did not increase in muscles of Smad2/3-deficient mice following denervation. We also demonstrate that serum starvation promotes Smad2/3 protein accumulation in C2C12 myogenic cells, an in vitro muscle atrophy model, an effect inhibited by IGF1 treatment. In vivo, we observed IGF1 receptor deactivation in immobilized muscle, even in the presence of normal levels of circulating IGF1. Denervation-induced muscle atrophy was accompanied by reduced glucose intake and elevated levels of branched-chain amino acids, effects that were Smad2/3-dependent. Thus, muscle immobilization attenuates IGF1 signals at the receptor rather than the ligand level, leading to Smad2/3 protein accumulation, muscle atrophy, and accompanying metabolic changes.

The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation

“…Denervation was observed to increase phosphorylation of AMPK␣2 and decrease phosphorylation of FoxO3, whereas ablation of AMPK␣2 protects against wasting and reversed the effect on FoxO3 (32). Another study found that Smad2/3 protein levels but not mRNA levels are increased in denervation independent of myostatin levels and that muscle-specific ablation of Smad2/3 is protective against atrophy (107). During disuse, mitochondrial reactive oxygen species (ROS) production leads to mitochondrial dysfunction and muscle atrophy (71).…”

Muscle atrophy and regeneration associated with behavioural loss and recovery of function after sciatic nerve crush

“…The atrophy is executed mainly by regulated proteolysis of contractile proteins through the proteasome but also autophagy‐lysosomal breakdown of other redundant myofibre constituents occur in parallel . The signalling pathways governing contractile protein breakdown is normally active and balanced by stimuli to increase myosins to enlarge myofibre size and muscle mass . Originating from theory that the DNA of a nucleus can support but a limited cellular volume and that this relationship sets a ceiling for growth (; myonuclear domain, MND), major alteration in fibre size should be accompanied by either a reduction of total number of myonuclei or the recruitment and incorporation of de novo formed myonuclei deriving from the regional stem cell niche, ie, Satellite cell (SC) niche .…”

“…We have used the nerve crush model to study the responses to denervation and the following re‐innervation in target hind limb muscles of the Sprague‐Dawley (SD) rat. This model may be useful in exploring details of muscle atrophy in response to denervation but also muscle regeneration because of re‐innervation . Further advantages of this model are that the insult recovery process may be assessed by behavioural testing, and that there is a reliable and high degree of un‐intrusive muscle function recovery across a few weeks owing to that the nerve conduit remains in continuity despite the crush insult ( idem ).…”

MicroRNA‐323‐3p promotes myogenesis by targeting Smad2

“…It is phosphorylated by the TGF‐β receptors to regulate other processes . Previous studies showed that Smad2 has a significant role in skeletal muscle development . Smad transcription factors regulate the expression of myostatin and control the growth and differentiation of myoblasts .…”

“…[22][23][24] Previous studies showed that Smad2 has a significant role in skeletal muscle development. 25,26 Smad transcription factors regulate the expression of myostatin and control the growth and differentiation of myoblasts. [27][28][29] Furthermore, some genes regulate myogenesis through the Smad2 signaling pathway.…”