Individuals with high skeletal muscle mitochondrial content have a lower risk to acquire cardiovascular and metabolic disease, obesity, and type II diabetes. Regular endurance training increases mitochondrial density through a complex network of transcriptional regulators that in an accumulated way are affected by each single exercise bout. The aim of the present study was to investigate the effect of a single exercise bout on the levels of PGC-1α and related regulatory factors important for the initial phase of skeletal muscle adaptation. Ten men and ten women were randomized to either an exercise group (60 min cycling at a work load corresponding to 70% of peak oxygen uptake) or a nonexercising control group. Skeletal muscle biopsies were taken before, at 30 min, and at 2, 6, and 24 h after the intervention. Twenty-two mRNA transcripts and five proteins were measured. With exercise, protein levels of PGC-1α-ex1b increased, and this elevation occurred before that of total PGC-1α protein. We also demonstrated the existence and postexercise expression pattern of two LIPIN-1 (LIPIN-1α and LIPIN-1β) and three NCoR1 (NCoR1-1, NCoR1-2, and NCoR1-3) isoforms in human skeletal muscle. The present study contributes new insights into the initial signaling events following a single bout of exercise and emphasizes PGC-1α-ex1b as the most exercise-responsive PGC-1α isoform.

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.

Advanced chronic kidney disease (CKD) is characterized by a premature aging phenotype of multifactorial origin. Mitochondrial dysfunction is prevalent in CKD and has been proposed as a major contributor to poor muscle function. Although the mitochondria-derived peptides (MDPs) humanin and mitochondrial open reading frame of 12S rRNA-c (MOTS-c) are involved in cell survival, suppression of apoptosis, and glucose control, the implications of MDP in CKD are unknown. We investigated humanin and MOTS-c protein expression in skeletal muscle and serum levels in CKD at stage 5 (glomerular filtration rate: <15 ml/min) patients and age-matched controls with normal renal function. Whereas circulating levels of humanin were increased in CKD, local muscle expression was reduced. In contrast, MOTS-c levels were reduced in both skeletal muscle and serum in CKD. Humanin in serum correlated positively to circulating TNF levels. Reduced MDP levels in skeletal muscle were associated with lower mitochondrial density and evidence of oxidative stress. These results indicate a differential regulation of MDPs in CKD and suggest an alternative site for humanin production than skeletal muscle in the uremic milieu. MDP levels were linked to systemic inflammation and evidence of oxidative stress in the muscle, two hallmark features of premature aging and uremia.

This article is available online at http://www.jlr.org breast cancer and/or tumorigenesis in reproductive tissues ( 3 ). The BRCA1 gene produces either a full-length breast cancer type 1 susceptibility protein (BRCA1) or through alternatively splicing two documented variants, BRCA1 ⌬ 11 or BRCA1 ⌬ 11b, both of which lack a nuclear localization signal ( 4 ). Recently, BRCA1 was identifi ed as a regulator of lipid metabolism in human breast cancer cells (MCF7) as a result of direct interaction with the phosphorylated form of acetylCoA carboxylase (ACC-p) at the BRCA1 C-terminal (BRCT) domains ( 5, 6 ). The interaction encourages the maintenance of the phosphorylated state of ACC thereby altering lipid metabolism in the cancer cell line ( 5, 6 ).ACC has two isoforms, ACC1 or ACC2, with ACC2 containing an extra 146 amino acids in the NH 2 -terminal region. ACC activity is negatively regulated by phosphorylation of residue Ser 79 on ACC1 and Ser 221 on ACC2 ( 7,8 ). In the active form (i.e., dephosphorylated), ACC catalyzes the carboxylation of acetyl-CoA into malonyl-CoA (MaCoA). Changes in cellular MaCoA content alter intracellular lipid dynamics in two specifi c manners ( 9, 10 ). MaCoA directly contributes to de novo synthesis of palmitate via FAS and MaCoA also allosterically inhibits carnitine palmitoyltransferase-1 (CPT-1), a mitochondrial long chain fatty acid transporter ( 11 ). Thus, in mammary tissue the ability of BRCA1 to affect ACC activity alters cellular lipid concentrations by indirectly regulating rates of fatty acid synthesis and/or the fl ux of fatty acids into the mitochondria.Abstract Breast cancer type 1 (BRCA1) susceptibility protein is expressed across multiple tissues including skeletal muscle. The overall objective of this investigation was to defi ne a functional role for BRCA1 in skeletal muscle using a translational approach. For the fi rst time in both mice and humans, we identifi ed the presence of multiple isoforms of BRCA1 in skeletal muscle. In response to an acute bout of exercise, we found increases in the interaction between the native forms of BRCA1 and the phosphorylated form of acetyl-CoA carboxylase. Decreasing BRCA1 content using a shRNA approach in cultured primary human myotubes resulted in decreased oxygen consumption by the mitochondria and increased reactive oxygen species production. The decreased BRCA1 content also resulted in increased storage of intracellular lipid and reduced insulin signaling. These results indicate that BRCA1 plays a critical role in the regulation of metabolic function in skeletal muscle. Collectively, these data reveal BRCA1 as a novel target to consider in our understanding of metabolic function and risk for development of metabolic-based diseases. -Jackson, K. C., E-K. Gidlund, J. Abbreviations: ACC, acetyl-CoA carboxylase; ACC-p, phosphorylated form of acetyl-CoA carboxylase; AICAR, 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide; AMPK, AMP-activated protein kinase; BRCA1, Breast Cancer 1, early onset; BRCA1 MG KO, mammary gland tissue fr...

Chronic kidney disease (CKD), which affects 10%-15% of the population, associates with a range of complications-such as cardiovascular disease, frailty, infections, muscle and bone disorders and premature ageing-that could be related to alterations of mitochondrial number, distribution, structure and function. As mitochondrial biogenesis, bioenergetics and the dynamic mitochondrial networks directly or indirectly regulate numerous intra-and extracellular functions, the mitochondria have emerged as an important target for interventions aiming at preventing or improving the treatment of complications in CKD. In this review, we discuss the possible role of bioactive food compounds and exercise in the modulation of the disturbed mitochondrial function in a uraemic milieu.

Dutta and co-workers suggest in a recent letter (1) that the SARS-CoV-2 nucleoprotein (N) might be a good vaccine target.…

Mitochondrial derived peptides (MDPs) humanin (HN) and mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) are involved in cell survival, suppression of apoptosis and metabolism. Circulating levels of MDPs are altered in chronic diseases such as diabetes type 2 and chronic kidney disease. Whether acute resistance (RE) or endurance (EE) exercise modulates circulating levels of HN and MOTS-c in humans is unknown. Following familiarization, subjects were randomized to EE (n=10, 45 min cycling at 70% of estimated VO2max), RE (n=10, 4 sets x 7RM, leg press and knee extension), or control (CON, n=10). Skeletal muscle biopsies and blood samples were collected before and at 30 minutes and 3 hours following exercise. Plasma concentration of HN and MOTS-c, skeletal muscle MOTS-c as well as gene expression of exercise related genes were analyzed. Acute EE and RE promoted changes in skeletal muscle gene expression typically seen in response to each exercise modality (c-Myc, 45S pre-rRNA, PGC-1α-total and PGC-1α-ex1b). At rest, circulating levels of HN were positively correlated to MOTS-c levels and age. Plasma levels of MDPs were not correlated to fitness outcomes (VO2max, leg strength or muscle mitochondrial (mt) DNA copy number). Circulating levels of HN were significantly elevated by acute EE but not RE. MOTS-C levels showed a trend to increase after EE. These results indicate that plasma MDP levels are not related to fitness status but that acute EE increases circulating levels of MDPs, in particular HN.

Irisin is a myokine that is thought to be secreted in response to exercise that may help to prevent obesity and maintain normal glucose metabolism. In this study we investigated the associations between irisin and glucose homeostasis in middle-aged, overweight and obese men (n =  144) with impaired glucose regulation, and the impact of exercise training on these relationships. The participants underwent 12 weeks of resistance or aerobic (Nordic walking) exercise training three times per week, 60 minutes per session. Venous blood (n = 105) and skeletal muscle samples (n = 45) were obtained at baseline and post-intervention. Compared to controls, Nordic walking, but not resistance training, increased irisin levels in plasma (9.6 ± 4.2%, P = 0.014; 8.7 ±  4.9%, P = 0.087; respectively) compared to controls. When considering all subjects, baseline irisin correlated positively with atherogenic index of plasma (r = 0.244, P = 0.013) and 2-hour insulin levels (r = 0.214, P = 0.028), and negatively with age (r = -0.262, P = 0.007), adiponectin (r = -0.240, P = 0.014) and McAuley index (r = -0.259, P = 0.008). Training-induced FNDC5 mRNA changes were negatively correlated with HbA1c (r = -0.527, P = 0.030) in the resistance training group and with chemerin in the Nordic walking group (r = -0.615, P = 0.033). In conclusion, 12-weeks of Nordic walking was more effective than resistance training in elevating plasma irisin, in middle-aged men with impaired glucose tolerance. Thus, the change in irisin in response to exercise training varied by the type of exercise but showed limited association with improvements in glucose homeostasis.