Effects of 3 days unloading on molecular regulators of muscle size in humans

Abstract

Changes in skeletal muscle mass are controlled by mechanisms that dictate protein synthesis or degradation. The current human study explored whether changes in activation of the phosphoinositide 3-kinase (PI3K)-Akt1, p38, myostatin, and mRNA expression of markers of protein degradation and synthesis occur soon after withdrawal of weight bearing. Biopsies of the vastus lateralis muscle (VL) and soleus muscle (Sol) were obtained from eight healthy men before and following 3 days of unilateral lower limb suspension (ULLS). Akt1, Forkhead box class O (FOXO)-1A, FOXO-3A, p38, and eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) phosphorylation and protein levels and myostatin protein level were analyzed by Western blot. Levels of mRNA of IGF1, FOXO-1A, FOXO-3A, atrogin-1, MuRF-1, caspase-3, calpain-2, calpain-3, 4E-BP1, and myostatin were measured using real-time PCR. The amounts of phosphorylated Akt1, FOXO-1A, FOXO-3A, and p38 were unaltered (P>0.05) after ULLS. Similarly, mRNA levels of IGF1, FOXO-1A, FOXO-3A, caspase-3, calpain-2, and calpain-3 showed no changes (P>0.05). The mRNA levels of atrogin-1 and MuRF-1, as well as the mRNA and protein phosphorylation of 4E-BP1, increased (P<0.05) in VL but not in Sol. Both muscles showed increased (P<0.05) myostatin mRNA and protein following ULLS. These results suggest that pathways other than PI3K-Akt stimulate atrogin-1 and MuRF-1 expression within 3 days of ULLS. Alternatively, transient changes in these pathways occurred in the early phase of ULLS. The increased myostatin mRNA and protein expression also indicate that multiple processes are involved in the early phase of muscle wasting. Further, the reported difference in gene expression pattern across muscles suggests that mechanisms regulating protein content in human skeletal muscle are influenced by phenotype and/or function.

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

“…On the other hand, BCL-3 binding to the NF-κB p50-p50 homodimer is an alternative pathway promoting NF-κB activation [102]. Interestingly, the alternative NF-κB signaling is required for immobilization-induced skeletal muscle atrophy [102][103][104] [110,111]. The radical model used in rodent, i.e., hindlimb suspension, could explain the discrepancy with human experiment.…”

Increased inflammatory cytokine expression in the vastus lateralis of patients with knee osteoarthritis

“…This muscle atrophy is clinically important, because the knee extensor muscles play a role in maintaining the capacity to perform daily activities in patients with knee OA (5). In addition, the disuse and subsequent atrophy of the affected limb, due to increased inflammation and pain, may lead to a further increase in inflammation, as seen after bed rest (6) and lower limb suspension (7). However, few studies have analyzed the molecular alterations occurring within skeletal muscle (knee extensors) in this population, focusing on molecular pathways associated with inflammation and atrophy.…”

Prevention of Skeletal Muscle Wasting: Disuse Atrophy and Sarcopenia

“…iv. Unilateral lower limb suspension (ULLS) in humans: three days of ULLS led to increased myostatin transcript and protein levels [60].…”

“…Animal models: increased MAFbx and MuRF1 after hindlimb suspension [68] iii. Unilateral lower limb suspension (ULLS) in humans: three days of ULLS led to increased MAFbx and MuRF1 transcript levels [60]; increased MuRF1 after 10 days ULLS and decreased MAFbx and MuRF1 10-21 days of ULLS [69].…”

“…Nonetheless, human models of atrophy do not show the same relationship of FOXO with MAFbx and MuRF1 [eg [60]]. Therefore, to fully understand atrophy and sarcopenia, and before discussing the mechanisms behind potential interventions, it is necessary to elucidate an anabolic pathway, namely the IGF1-AKT-mTOR pathway.…”