iMS‐Bmal1^−/− mice show evident signs of sarcopenia that are counteracted by exercise and melatonin therapies

Abstract

Sarcopenia is an age‐related disease characterized by a reduction in muscle mass, strength, and function and, therefore, a deterioration in skeletal muscle health and frailty. Although the cause of sarcopenia is still unknown and, thus, there is no treatment, increasing evidence suggests that chronodisruption, particularly alterations in Bmal1 clock gene, can lead to those deficits culminating in sarcopenia. To gain insight into the cause and mechanism of sarcopenia and the protective effect of a therapeutic intervention with exercise and/or melatonin, the gastrocnemius muscles of male and female skeletal muscle‐specific and inducible Bmal1 knockout mice (iMS‐Bmal1−/−) were examined by phenotypic tests and light and electron microscopy. Our results revealed a disruption of the normal activity/rest rhythm, a drop in skeletal muscle function and mass, and increased frailty in male and female iMS‐Bmal1−/− animals compared to controls. A reduction in muscle fiber size and increased collagenous tissue were also detected, accompanied by reduced mitochondrial oxidative capacity and a compensatory shift towards a more oxidative fiber type. Electron microscopy further supports mitochondrial impairment in mutant mice. Melatonin and exercise ameliorated the damage caused by loss of Bmal1 in mutant mice, except for mitochondrial damage, which was worsened by the latter. Thus, iMS‐Bmal1−/− mice let us to identify Bmal1 deficiency as the responsible for the appearance of sarcopenia in the gastrocnemius muscle. Moreover, the results support the exercise and melatonin as therapeutic tools to counteract sarcopenia, by a mechanism that does not require the presence of Bmal1.

Skeletal muscle BMAL1 is necessary for transcriptional adaptation of local and peripheral tissues in response to endurance exercise training

“…Our results are suggestive of continued low glycolytic flux and upregulation of pathways required for TCA cycle anaplerosis and oxidative phosphorylation with exercise training. Consistent with these observations, we identified that both the nuclear and mitochondrial transcriptomes likely act to compensate for the metabolic dysregulation and mitochondrial disruption [12,29] in the iMSBmal1KO muscle with the extensive upregulation of TCA cycle enzymes and transporters, as well as oxidative phosphorylation/ mitochondrial components.…”

“…Here we assess the importance of the endogenous skeletal muscle TTFL for exercise adaptation through ablation of Bmal1 expression in adult myofibers, essentially terminating the core circadian TTFL [5]. The molecular and phenotypic changes downstream of loss of muscle BMAL1 have been well described previously[4,5,8,9,12,23,29].…”

“…Exercise training also directly impacts the circadian transcriptome, by increasing the number of clock output genes [21,22]. Various exercise performance measures such as strength and endurance capacity also present time-of-day differences, highlighting a likely role of the muscle clock in overall muscle function [21][22][23][24][25][26][27]. While it is clear that exercise and the skeletal muscle circadian TTFL are linked [4], the question of whether the muscle clock has any impact on either the acute response or training induced adaptations in skeletal muscle is yet to be elucidated.…”

From Chronodisruption to Sarcopenia: The Therapeutic Potential of Melatonin

“…To grasp the precise role of Bmal1 in skeletal muscle, several studies have been conducted in mice deficient in Bmal1 in skeletal muscle, including a recent study from our research group. These suggest that the Bmal1 gene is essential for preserving muscle function and structure and for mitochondrial maintenance, thus delaying frailty and sarcopenia [111,115,116]. Other researchers identified alterations in glucose metabolism and a decrease in GLUT4 levels in the muscle tissue of these mice [117].…”

“…Additionally, pineal melatonin production also experiences a significant decline with age [173], potentially leading to reduced circadian control and disruption of clock genes in various tissues. In multiple experimental conditions, including acute and chronic inflammation, aging, and sarcopenia, melatonin consistently enhanced endogenous antioxidant defense, reduced innate immunity activation, and stimulated mitochondria [38,78,88,89,115,158,[174][175][176][177][178]. Furthermore, melatonin was also shown to have the capacity to restore clock gene expression, which is altered in these pathologies, as well as in other conditions such as cancer or Parkinson's [179,180].…”