Preventing muscle wasting by osteoporosis drug alendronate in vitro and in myopathy models via sirtuin‐3 down‐regulation

Abstract

Background A global consensus on the loss of skeletal muscle mass and function in humans refers as sarcopenia and cachexia including diabetes, obesity, renal failure, and osteoporosis. Despite a current improvement of sarcopenia or cachexia with exercise training and supportive therapies, alternative and specific managements are needed to discover for whom are unable or unwilling to embark on these treatments. Alendronate is a widely used drug for osteoporosis in the elderly and postmenopausal women. Osteopenic menopausal women with 6 months of alendronate therapy have been observed to improve not only lumbar bone mineral density but also handgrip strength. However, the effect and mechanism of alendronate on muscle strength still remain unclear. Here, we investigated the therapeutic potential and the molecular mechanism of alendronate on the loss of muscle mass and strength in vitro and in vivo. Methods Mouse myoblasts and primary human skeletal muscle-derived progenitor cells were used to assess the effects of low-dose alendronate (0.1-1 μM) combined with or without dexamethasone on myotube hypertrophy and myogenic differentiation. Moreover, we also evaluated the effects of low-dose alendronate (0.5 and 1 mg/kg) by oral administration on the limb muscle function and morphology of mice with denervation-induced muscle atrophy and glycerol-induced muscle injury. Results Alendronate inhibited dexamethasone-induced myotube atrophy and myogenic differentiation inhibition in mouse myoblasts and primary human skeletal muscle-derived progenitor cells. Alendronate significantly abrogated dexamethasone-up-regulated sirtuin-3 (SIRT3), but not SIRT1, protein expression in myotubes. Both SIRT3 inhibitor AKG7 and SIRT3-siRNA transfection could also reverse dexamethasone-up-regulated atrogin-1 and SIRT3 protein expressions. Animal studies showed that low-dose alendronate by oral administration ameliorated the muscular malfunction in mouse models of denervation-induced muscle atrophy and glycerol-induced muscle injury with a negative regulation of SIRT3 expression. Conclusions The putative mechanism by which muscle atrophy was improved with alendronate might be through the SIRT3 down-regulation. These findings suggest that alendronate can be a promising therapeutic strategy for management of muscle wasting-related diseases and sarcopenia.

Sirtuin 3 deficiency does not impede digit regeneration in mice

“…It may be that given the integral role of inflammation in regeneration the intact macrophage response in the knockout strain may be more indicative of the role of SIRT3 in regeneration. Our data support the development of potential therapies that may target SIRT3 56 with the anticipation that they would have little impact on bone regeneration. Our findings are important to both the digit regeneration field and in the developing field of sirtuin research in that they highlight the complexity of resolving a single gene function in the context of complex processes such as bone and soft tissue regeneration in vivo .…”

The Versatility of Sirtuin-1 in Endocrinology and Immunology

“…Therefore, SIRT1 and GR interaction controls the metabolic state of cells, acting as an energy sensor via cellular NAD/NADH regulation and linking the transcriptional parameters of metabolic genes to the stress response. SIRT1 is involved in preventing glucocorticoid induced muscle wasting and mitochondrial dysfunction as reported by many researchers (Knobloch et al, 2014;Poulsen et al, 2014;Chiu et al, 2018;Ma et al, 2019). Resveratrol prevented dexamethasone-induced acetylation of FOXO1, expression of atrogin-1 and muscle ring finger protein-1 (MuRF1), and protein degradation in cultured myotubes in a SIRT1 dependent manner (Alamdari et al, 2012).…”

Inhibited inositol monophosphatase and decreased myo‐inositol concentration improve wasting in skeletal muscles

“…Therefore, 10 μM ebselen, 10 μM L‐690330, and 5 mM LiCl were selected. The dexamethasone model was used to measure myotube wasting 6 . Myotubes treated with ebselen and dexamethasone had higher average diameter and increased proportion of larger myotubes compared to those treated with dexamethasone alone (Figure 1C,D and Figure S1E).…”

“…Further assessment of the therapeutic effect of ebselen on muscle wasting was conducted in the glycerol model, which has been used in previous studies of drugs repurposed for muscle wasting. 6 Ebselen has been approved as an oral medication in humans. Glycerol delivery increased myo-inositol level in the gastrocnemius muscle and was reduced by ebselen treatment ( Figure S7A).…”

“…Expression of FoxO3a target atrogenes, atrogin‐1 and MuRF‐1, in the quadriceps was increased by dexamethasone treatment and reduced by cotreatment with ebselen (Figure S6C). Further assessment of the therapeutic effect of ebselen on muscle wasting was conducted in the glycerol model, which has been used in previous studies of drugs repurposed for muscle wasting 6 . Ebselen has been approved as an oral medication in humans.…”