Juha J. Hulmi

Are skeletal muscle FNDC5 gene expression and irisin release regulated by exercise and related to health

•  Contradictory findings have been reported concerning the function of irisin and its precursor gene, skeletal muscle FNDC5, in energy homeostasis and metabolic health, and the associated regulatory role of exercise and PGC‐1α. •  We analysed the effects of different short‐ and long‐term exercise regimens on muscle FNDC5 and PGC‐1α, and serum irisin, and studied the associations of irisin and FNDC5 with health parameters. •  FNDC5 and serum irisin did not change after acute aerobic, long‐term endurance training or endurance training combined with resistance exercise (RE) training, or associate with metabolic disturbances. A single RE bout increased FNDC5 mRNA in young, but not older men (27 vs. 62 years). Changes in PGC‐1α or serum irisin were not consistently accompanied by changes in FNDC5. •  Our data suggest that the effects of exercise on FNDC5 and irisin are not consistent, and that their role in health is questionable. Moreover, the regulatory mechanisms should be studied further.

Effect of protein/essential amino acids and resistance training on skeletal muscle hypertrophy: A case for whey protein

Regardless of age or gender, resistance training or provision of adequate amounts of dietary protein (PRO) or essential amino acids (EAA) can increase muscle protein synthesis (MPS) in healthy adults. Combined PRO or EAA ingestion proximal to resistance training, however, can augment the post-exercise MPS response and has been shown to elicit a greater anabolic effect than exercise plus carbohydrate. Unfortunately, chronic/adaptive response data comparing the effects of different protein sources is limited. A growing body of evidence does, however, suggest that dairy PRO, and whey in particular may: 1) stimulate the greatest rise in MPS, 2) result in greater muscle cross-sectional area when combined with chronic resistance training, and 3) at least in younger individuals, enhance exercise recovery. Therefore, this review will focus on whey protein supplementation and its effects on skeletal muscle mass when combined with heavy resistance training.

Resistance exercise with whey protein ingestion affects mTOR signaling pathway and myostatin in men

Signaling pathways sense local and systemic signals and regulate muscle hypertrophy. The effects of whey protein ingestion on acute and long-term signaling responses of resistance exercise are not well known. Previously untrained young men were randomized into protein (n = 9), placebo (n = 9), and control (n = 11) groups. Vastus lateralis (VL) muscle biopsies were taken before and 1 h and 48 h after a leg press of 5 x 10 repetitions [resistance exercise (RE)] and after 21 wk (2 times per week) of resistance training (RT). Protein (15 g of whey) or nonenergetic placebo was ingested before and after a single RE bout and each RE workout throughout the RT. The protein group increased its body mass and VL muscle thickness (measured by ultrasonography) already at week 10.5 (P < 0.05). At week 21, the protein and placebo groups had similarly increased their myofiber size. No changes were observed in the nonexercised controls. However, the phosphorylation of p70(S6K) and ribosomal protein S6 (rpS6) were increased at 1 h post-RE measured by Western blotting, the former being the greatest with protein ingestion. Mammalian target of rapamycin (mTOR) phosphorylation was increased after the RE bout and RT only in the protein group, whereas the protein ingestion prevented the post-RE decrease in phosphorylated eukaryotic initiation factor 4E binding protein 1 (p-4E-BP1). Akt phosphorylation decreased after RT, whereas no change was observed in phosphorylated eukaryotic elongation factor 2. A post-RE decrease in muscle myostatin protein occurred only in the placebo group. The results indicate that resistance exercise rapidly increases mTOR signaling and may decrease myostatin protein expression in muscle and that whey protein increases and prolongs the mTOR signaling response.

VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart.

Angiogenic growth factors have recently been linked to tissue metabolism. We have used genetic gain‐ and loss‐of function models to elucidate the effects and mechanisms of action of vascular endothelial growth factor‐B (VEGF‐B) in the heart. A cardiomyocyte‐specific VEGF‐B transgene induced an expanded coronary arterial tree and reprogramming of cardiomyocyte metabolism. This was associated with protection against myocardial infarction and preservation of mitochondrial complex I function upon ischemia‐reperfusion. VEGF‐B increased VEGF signals via VEGF receptor‐2 to activate Erk1/2, which resulted in vascular growth. Akt and mTORC1 pathways were upregulated and AMPK downregulated, readjusting cardiomyocyte metabolic pathways to favor glucose oxidation and macromolecular biosynthesis. However, contrasting with a previous theory, there was no difference in fatty acid uptake by the heart between the VEGF‐B transgenic, gene‐targeted or wildtype rats. Importantly, we also show that VEGF‐B expression is reduced in human heart disease. Our data indicate that VEGF‐B could be used to increase the coronary vasculature and to reprogram myocardial metabolism to improve cardiac function in ischemic heart disease.

Vitamin C and E supplementation alters protein signalling after a strength training session, but not muscle growth during 10 weeks of training

Although antioxidant supplements are generally believed to give health benefits, recent experiments show that they may adversely affect adaptations to endurance exercise. This study is the first to investigate the effects of high dosages of vitamins C and E on the cellular and physiological adaptations to strength training in humans. Here we report that vitamin C and E supplementation interfered with exercise‐induced signalling in muscle cells after a session of strength training, by reducing the phosphorylation of p70S6 kinase and mitogen‐activated protein kinases p38 and ERK1/2. The vitamin C and E supplement did not significantly blunt muscle hypertrophy during 10 weeks of training; however, some measurements of muscle strength revealed lower increases in the supplemented group than the placebo group. Even though the cellular events are not clearly reflected in physiological and performance measurements, this study implies that redox signalling is important for inducing skeletal muscle adaptations to strength training and that vitamin C and E supplements in high dosages should be avoided by healthy, young individuals engaged in strength training.

Effects of alfa-hydroxy-isocaproic acid on body composition, DOMS and performance in athletes

BackgroundAlfa-Hydroxy-isocaproic acid (HICA) is an end product of leucine metabolism in human tissues such as muscle and connective tissue. According to the clinical and experimental studies, HICA can be considered as an anti-catabolic substance. The present study investigated the effects of HICA supplementation on body composition, delayed onset of muscle soreness (DOMS) and physical performance of athletes during a training period.MethodsFifteen healthy male soccer players (age 22.1+/-3.9 yr) volunteered for the 4-week double-blind study during an intensive training period. The subjects in the group HICA (n = 8) received 583 mg of sodium salt of HICA (corresponding 500 mg of HICA) mixed with liquid three times a day for 4 weeks, and those in the group PLACEBO (n = 7) received 650 mg of maltodextrin mixed with liquid three times a day for the same period. According to a weekly training schedule, they practiced soccer 3 - 4 times a week, had strength training 1 - 2 times a week, and had one soccer game during the study. The subjects were required to keep diaries on training, nutrition, and symptoms of DOMS. Body composition was evaluated with a dual-energy X-ray absorptiometry (DXA) before and after the 4-week period. Muscle strength and running velocity were measured with field tests.ResultsAs compared to placebo, the HICA supplementation increased significantly body weight (p < 0.005) and whole lean body mass (p < 0.05) while fat mass remained constant. The lean body mass of lower extremities increased by 400 g in HICA but decreased by 150 g in PLACEBO during the study. This difference between the groups was significant (p < 0.01). The HICA supplementation decreased the whole body DOMS symptoms in the 4th week of the treatment (p < 0.05) when compared to placebo. Muscle strength and running velocity did not differ between the groups.ConclusionAlready a 4-week HICA supplementation of 1.5 g a day leads to small increases in muscle mass during an intensive training period in soccer athletes.

Altered REDD1, myostatin, and Akt/mTOR/FoxO/MAPK signaling in streptozotocin-induced diabetic muscle atrophy.

Type 1 diabetes, if poorly controlled, leads to skeletal muscle atrophy, decreasing the quality of life. We aimed to search highly responsive genes in diabetic muscle atrophy in a common diabetes model and to further characterize associated signaling pathways. Mice were killed 1, 3, or 5 wk after streptozotocin or control. Gene expression of calf muscles was analyzed using microarray and protein signaling with Western blotting. We identified translational repressor protein REDD1 (regulated in development and DNA damage responses) that increased seven- to eightfold and was associated with muscle atrophy in diabetes. The diabetes-induced increase in REDD1 was confirmed at the protein level. This result was accompanied by the increased gene expression of DNA damage/repair pathways and decreased expression in ATP production pathways. Concomitantly, increased phosphorylation of AMPK and dephosphorylation of the Akt/mTOR/S6K1/FoxO pathway of proteins were observed together with increased protein ubiquitination. These changes were especially evident during the first 3 wk, along with the strong decrease in muscle mass. Diabetes also induced an increase in myostatin protein and decreased MAPK signaling. These, together with decreased serum insulin and increased serum glucose, remained altered throughout the 5-wk period. In conclusion, diabetic myopathy induced by streptozotocin led to alteration of multiple signaling pathways. Of those, increased REDD1 and myostatin together with decreased Akt/mTOR/FoxO signaling are associated with diabetic muscle atrophy. The increased REDD1 and decreased Akt/mTOR/FoxO signaling followed a similar time course and thus may be explained, in part, by increased expression of genes in DNA damage/repair and possibly also decrease in ATP-production pathways.

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

Loss of muscle mass and function occurs in various diseases. Myostatin blocking can attenuate muscle loss, but downstream signaling is not well known. Therefore, to elucidate associated signaling pathways, we used the soluble activin receptor IIb (sActRIIB-Fc) to block myostatin and activins in mice. Within 2 wk, the treatment rapidly increased muscle size as expected but decreased capillary density per area. sActRIIB-Fc increased muscle protein synthesis 1-2 days after the treatment correlating with enhanced mTORC1 signaling (phosphorylated rpS6 and S6K1, r = 0.8). Concurrently, increased REDD1 and eIF2Bε protein contents and phosphorylation of 4E-BP1 and AMPK was observed. In contrast, proangiogenic MAPK signaling and VEGF-A protein decreased. Hippo signaling has been characterized recently as a regulator of organ size and an important regulator of myogenesis in vitro. The phosphorylation of YAP (Yes-associated protein), a readout of activated Hippo signaling, increased after short- and longer-term myostatin and activin blocking and in exercised muscle. Moreover, dystrophic mdx mice had elevated phosphorylated and especially total YAP protein content. These results show that the blocking of myostatin and activins induce rapid skeletal muscle growth. This is associated with increased protein synthesis and mTORC1 signaling but decreased capillary density and proangiogenic signaling. It is also shown for the first time that Hippo signaling is activated in skeletal muscle after myostatin blocking and exercise and also in dystrophic muscle. This suggests that Hippo signaling may have a role in skeletal muscle in various circumstances.

Molecular signaling in muscle is affected by the specificity of resistance exercise protocol

Mammalian target of rapamycin and mitogen‐activated protein kinase (MAPK) signaling pathways have been highlighted as important for muscle adaptations and thus, they may distinguish adaptations to different exercises. Typically, resistance exercise designed for muscle hypertrophy has moderate intensity (60–80% of one repetition maximum, 1 RM) while one prioritizing maximal strength with minor hypertrophy has a higher intensity (≥90% of 1 RM). Eight untrained men (28.4±3.7 years) conducted two different bilateral leg press exercise protocols: hypertrophic (5 × 10 RM) and pure maximal strength (15 × 1 RM) in a counterbalanced, cross‐over design with 1 week between exercises. Vastus lateralis muscle biopsies were taken before and 0.5 h after resistance exercise, or in six controls (26.5±3.6 years) who rested. The phosphorylation of p70S6K (Thr421/Ser424), rpS6 (Ser240/244 and Ser235/236) and MAPK p38 as increased (∼2–16 fold) after both exercise protocols. However, the phosphorylation of MAPK Erk1/2 and p70S6K at Thr389 increased only after 5 × 10 RM. The increase in the phosphorylation of p70S6K (Thr421/Ser424), rpS6 (Ser235/236) and Erk1/2 were higher after 5 × 10 RM (P<0.05). No changes were seen in controls. In conclusion, MAPK signaling is greater after hypertrophic than maximal strength exercise protocol. This may mediate adaptations specific to these different types of training regimens.

Heavy resistance exercise training and skeletal muscle androgen receptor expression in younger and older men.

Effects of heavy resistance exercise on serum testosterone and skeletal muscle androgen receptor (AR) concentrations were examined before and after a 21-week resistance training period. Seven healthy untrained young adult men (YT) and ten controls (YC) as well as ten older men (OT) and eight controls (OC) volunteered as subjects. Heavy resistance exercise bouts (5 × 10 RM leg presses) were performed before and after the training period. Muscle biopsies were obtained before and 1h and 48 h after the resistance exercise bouts from m.vastus lateralis (VL) to determine cross-sectional area of muscle fibers (fCSA) and AR mRNA expression and protein concentrations. No changes were observed in YC and OC while resistance training led to significant increases in maximal strength of leg extensors (1 RM), fCSA and lean body mass in YT and OT. Acute increases occurred in serum testosterone concentrations due to resistance exercises but basal testosterone remained unaltered. Mean AR mRNA expression and protein concentration remained unchanged after heavy resistance exercise bouts compared to pre-values. The individual pre- to post-training changes in resting (pre-exercise) AR protein concentration correlated with the changes in fCSA and lean body mass in the combined group of YT and OT. Similarly, it correlated with the changes in 1 RM in YT. Although mean AR expression did not changed due to the resistance exercise training, the present findings suggest that the individual changes of AR protein concentration in skeletal muscle following resistance training may have an impact on training-induced muscular adaptations in both younger and older men.