Abstract
The clear mechanism of moderate exercise training (Ex) in attenuating muscle loss remains elusive in diabetes. We investigated the effects of moderate exercise training on diabetes-induced nuclear factor-κB (NF-κB) activation and mitochondrial dysfunction. Skeletal muscle size and atrophy signaling pathways were examined in type 2 diabetic db/db mice with or without moderate exercise training (5.2 m/min, 1 h/day, and 5 days/week for a total of 8 weeks). Exercise training decreased serum leptin, MCP-1, and resistin levels in db/db+Ex mice, but it did not reduce symptoms of insulin resistance including hyperglycemia, hyperinsulinemia, and impaired glucose tolerance. Moderate exercise training prevented the loss of muscle mass of tibialis anterior and gastrocnemius muscles in db/db+Ex mice. The average cross-sectional area of tibialis anterior muscle was increased significantly in db/db+Ex mice compared with untrained mice (830.6 vs. 676.5 μm2). Inhibition of MuRF-1 and K48-linked polyubiquitination was observed in db/db+Ex mice. Exercise training reduced activation of IκBα/NF-κB pathway and lowered IL-6, TNFα, F4/80 (macrophage marker) at mRNA level in db/db+Ex mice compared with untrained mice. Exercise training did not influence FoxO3a phosphorylation and its upstream regulator Akt. Exercise training increased SIRT1 and PGC1α expression and AMPKα and mitochondrial complex IV activities and upregulated genes involved in mitochondrial biogenesis/function including Nrf1, Tfam, and mitochondrial complexes I–V. In conclusion, moderate exercise training inhibits NFκB signaling and activates SIRT1-AMPKα-PGC1α axis, thereby attenuating type 2 diabetes-related muscle atrophy.
Highlights
Certain metabolic disorders such as diabetes and obesity are involved in the development of muscle atrophy, a decrease in the mass of skeletal muscle (Kalyani et al, 2014; Le et al, 2014)
Mitochondrial dysfunction accompanied by generation of excessive reactive oxygen species contributes to elevated oxidative stress (Zorov et al, 2014) that leads to impaired skeletal muscle function and accelerated loss of muscle mass in many diseases such as disuse/inactivity, diabetes, cancer, and sarcopenia (Romanello and Sandri, 2015; Joseph et al, 2016)
Increased fasting glucose and serum insulin levels were observed in db/db and db/db+Ex compared with m/m mice (Figures 1B,C)
Summary
Certain metabolic disorders such as diabetes and obesity are involved in the development of muscle atrophy, a decrease in the mass of skeletal muscle (Kalyani et al, 2014; Le et al, 2014). Transcriptional factors, NF-κB and FoxO3a translocate into nucleus and subsequently upregulate transcriptional activities of MuRF-1 under certain pathological conditions (Cai et al, 2004; Gumucio and Mendias, 2013; Perry et al, 2016). This suggests that inhibition of NF-κB and/or FoxO3a pathways is a promising target for preventing muscle atrophy. Restoration of mitochondrial function is critical for maintaining skeletal muscle homeostasis
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