Adverse effects of acrolein, a ubiquitous environmental toxicant, on muscle regeneration and mass

Abstract

Background Acrolein is an extremely electrophilic aldehyde. Increased urinary acrolein adducts have been found in type 2 diabetic patients and people with a smoking habit. The increased blood acrolein was shown in patients who received the cancer drug cyclophosphamide. Both diabetes and smoking are risk factors for skeletal muscle wasting or atrophy. Acrolein has been found to induce myotube atrophy in vitro . The in vitro and in vivo effects and mechanisms of acrolein on myogenesis and the in vivo effect of acrolein on muscle wasting still remain unclear. Methods C2C12 myoblasts were used to assess the effects of low‐dose acrolein (0.125–1 μM) on myogenesis in vitro . Mice were exposed daily to acrolein in distilled water by oral administration (2.5 and 5 mg/kg) for 4 weeks with or without glycerol‐induced muscle injury to investigate the effects of acrolein on muscle wasting and regeneration. Results Non‐cytotoxic‐concentration acrolein dose dependently inhibited myogenic differentiation in myoblasts (myotube formation inhibition: 0.5 and 1 μM, 66.25% and 46.25% control, respectively, n = 4, P < 0.05). The protein expression for myogenesis‐related signalling molecules (myogenin and phosphorylated Akt: 0.5 and 1 μM, 85.15% and 51.52% control and 62.63% and 56.57% control, respectively, n = 4, P < 0.05) and myosin heavy chain (MHC: 0.5 and 1 μM, 63.64% and 52.53% control, n = 4, P < 0.05) were decreased in acrolein‐treated myoblasts. Over‐expression of the constitutively active form of Akt in myoblasts during differentiation prevented the inhibitory effects of acrolein (1 μM) on myogenesis (MHC and myogenin protein expression: acrolein with or without constitutively active Akt, 64.65% and 105.21% control and 69.14% and 102.02% control, respectively, n = 5, P < 0.05). Oral administration of acrolein for 4 weeks reduced muscle weights (5 mg/kg/day: 65.52% control, n = 6, P < 0.05) and cross‐sectional area of myofibers in soleus muscles (5 mg/kg/day: 79.92% control, n = 6, P < 0.05) with an up‐regulation of atrogin‐1 and a down‐regulation of phosphorylated Akt protein expressions. Acrolein retarded soleus muscle regeneration in a glycerol‐induced muscle regeneration mouse model (5 mg/kg/day: 49.29% control, n = 4, P < 0.05). Acrolein exposure reduced muscle endurance during rotarod fatigue performance in mice with or without glycerol‐induced muscle injury (5 mg/kg/day without glycerol: 30.43% control, n ...

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“…Since acrolein induces myotube atrophy in vitro, and acrolein-inhalable cigarette smoking serve as major risk factors for skeletal muscle deterioration (atrophy), a very recent investigation [105] focused on the mechanism of this phenomenon discovered that low doses of this aldehyde significantly inhibited myogenic differentiation in vitro, a process which may occur through suppression of the serine-threonine protein kinase (Akt) signalling pathway. Mice with or without glycerol-induced muscle injury were exposed to 2.5 and 5 mg/kg BW/day acrolein in distilled water via the oral route for 4 weeks in order to investigate its effects on muscle wasting and regeneration.…”

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“…ACR remarkably increased plasma levels of atherogenic cholesterol and low-density lipoprotein cholesterol [7]. ACR promoted cellular redox imbalance and elevated oxidative stress in cardiomyocytes, and ACR also activated the inflammatory response that elevated the risk of the development of heart disease [5, 7]. ACR led to foam cell formation and accelerated the atherosclerotic plaque lesions and the development of atherosclerosis by increasing inflammatory response and inhibiting the reverse cholesterol transport process [29].…”

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“…TLR4 was expressed on the membranes of macrophages that promoted proinflammatory signaling and played a key role in the development of coronary atherosclerosis [3, 4]. Acrolein (ACR) promoted inflammatory response and oxidative stress response [5, 6]. ACR promoted dysregulation of cellular cholesterol transport genes and was a key heart disease risk factor.…”