Melatonin restores muscle regeneration and enhances muscle function after crush injury in rats

Abstract

The goal of this study was to provide evidence that melatonin improves muscle healing following blunt skeletal muscle injury. For this purpose, we used 56 rats and induced an open muscle injury. After injury, all animals received either daily melatonin or vehicle solution intraperitoneally. Subsequent observations were performed at day 1, 4, 7, and 14 after injury. After assessment of fast twitch and tetanic muscle force, we analyzed leukocyte infiltration, satellite cell number, and cell apoptosis. We further quantified the expression of the melatonin receptor and the activation of extracellular-signal-regulated kinase (ERK). Chronic treatment with melatonin significantly increased the twitch and tetanic force of the injured muscle at day 4, 7, and 14. At day 1, melatonin significantly reduced the leukocyte infiltration and significantly increased the number of satellite cells when compared to the control group. Consistent with this observation, melatonin significantly reduced the number of apoptotic cells at day 4. Furthermore, phosphorylation of ERK reached maximal values in the melatonin group at day 1 after injury. Additionally, we detected the MT1a receptor in the injured muscle and showed a significant up-regulation of the MT1a mRNA in the melatonin group at day 4. These data support the hypothesis that melatonin supports muscle restoration after muscle injury, inhibits apoptosis via modulation of apoptosis-associated signaling pathways, increases the number of satellite cells, and reduces inflammation.

Lipin1 Regulates Skeletal Muscle Differentiation through Extracellular Signal-regulated Kinase (ERK) Activation and Cyclin D Complex-regulated Cell Cycle Withdrawal

“…Consistent with what we observed, ERK1/2 is required for myoblast terminal differentiation and multinucleated muscle fiber formation (30). Activation of ERK signaling occurs at early stages of muscle regeneration (42,43) and in wound repair (43,44), suggesting that ERK phosphorylation has some beneficial effects. Phosphatidic acid accumulation in peripheral nerves of lipin1-deficient fld mice increases ERK1/2 activation, mediating Schwann cell dedifferentiation and proliferation (45).…”

Role of melatonin in the regulation of autophagy and mitophagy: A review

“…Since melatonin and autophagy are intimately related to oxidative stress levels, a relationship between them is anticipated. A role of melatonin in regulating apoptosis (programmed cell death type I) has been known for decades, including its differential actions in normal and cancer cells, i.e., melatonin increased apoptosis in cancer cells (Sainz et al, 2003;Motilva et al, 2011;Carbajo-Pescador et al, 2011) while reducing it in normal cells (Gobe and Crane, 2001;Sainz et al, 2003;Stratos et al, 2012). These contrasting findings are now widely accepted by the scientific community, since melatonin's role in modulating oxidative stress by different pathways (direct and indirect) can induce both cellular actions.…”

Impaired Skeletal Muscle Regeneration in the Absence of Fibrosis during Hibernation in 13-Lined Ground Squirrels

“…ERK signaling has previously been shown to play a role in regulating cell growth and repressing myoblast differentiation [37], [58], [59]. In addition, activation of ERK signaling may also have some beneficial effects on early stages of muscle regeneration [60] and in wound repair [61], [62]. Myostatin is a negative regulator of satellite cell activation, regeneration, and muscle growth [33], [34], [63], [64].…”