Humanin skeletal muscle protein levels increase after resistance training in men with impaired glucose metabolism

Abstract

Humanin (HN) is a mitochondrially encoded and secreted peptide linked to glucose metabolism and tissue protecting mechanisms. Whether skeletal muscle HN gene or protein expression is influenced by exercise remains unknown. In this intervention study we show, for the first time, that HN protein levels increase in human skeletal muscle following 12 weeks of resistance training in persons with prediabetes. Male subjects (n = 55) with impaired glucose regulation (IGR) were recruited and randomly assigned to resistance training, Nordic walking or a control group. The exercise interventions were performed three times per week for 12 weeks with progressively increased intensity during the intervention period. Biopsies from the vastus lateralis muscle and venous blood samples were taken before and after the intervention. Skeletal muscle and serum protein levels of HN were analyzed as well as skeletal muscle gene expression of the mitochondrially encoded gene MT‐RNR2, containing the open reading frame for HN. To elucidate mitochondrial training adaptation, mtDNA, and nuclear DNA as well as Citrate synthase were measured. Skeletal muscle HN protein levels increased by 35% after 12 weeks of resistance training. No change in humanin protein levels was seen in serum in any of the intervention groups. There was a significant correlation between humanin levels in serum and the improvements in the 2 h glucose loading test in the resistance training group. The increase in HN protein levels in skeletal muscle after regular resistance training in prediabetic males may suggest a role for HN in the regulation of glucose metabolism. Given the preventative effect of exercise on diabetes type 2, the role of HN as a mitochondrially derived peptide and an exercise‐responsive mitokine warrants further investigation.

Humanin is a novel regulator of Hedgehog signaling and prevents glucocorticoid‐induced bone growth impairment

“…In contrast, no clear growth plate phenotype was observed in HNtg mice, which could be due to the fact that HN levels were only slightly increased. A recent clinical study showed that only marginally increased HN levels are associated with improved blood glucose levels after resistance training in men with impaired glucose metabolism, suggesting that even a modest increase in circulating HN levels can exert positive effects (50).…”

Linking cellular stress responses to systemic homeostasis

“…These peptides, which are generally encoded by small, alternative reading frames of the mitochondrial genome, include humanin, multiple small humanin-like peptides (SHLPs) and mitochondrial-derived peptide MOTSc (also known as MTRNR1) 86 . Humanin not only favours proteostasis and has broad cytoprotective effects coupled to the activation of multiple variants of autophagy 87,88 but also may be involved in the regulation of systemic glucose homeostasis 89 . Along similar lines, MOTSc has been attributed a robust role in the preservation of organismal metabolic homeostasis, most likely reflecting its ability to trigger AMP-activated protein kinase (AMPK) activation in the skeletal muscle 90 .…”

Mitochondrially derived peptides as novel regulators of metabolism

“…Gidlund et al . () discovered that muscle humanin levels were increased during resistance training compared to control and aerobic exercise (Nordic walking), but circulating levels were not affected. The authors believed that this change could be due to humanin's role in glucose metabolism.…”