Exercise and Metabolic Health

The awareness that exercise is an essential means to maintain an adequate response to health challenges is increasing worldwide. Although whole body metabolism is governed by many organs that communicate to ascertain metabolic homeostasis, especially skeletal muscle is central in the response to metabolic changes, since it is the major site of glucose uptake and usage.

Thus, metabolic diseases related to poor lipid/glucose handling due to over-nutrition and insufficient physical activity often trace back to muscle metabolic dysfunction, and vice versa. There is evidence that local thyroid hormone levels in muscle are crucial for the response to exercise, and that metabolically-active thyroid hormones can be considered possible exercise mimetics.

Based on data obtained in rodents as well as humans, this short review aims to shedto light on why muscle metabolic integrity in response to exercise (increasingly studied in combination with restricted nutrition) is crucial for health, rangingfrom mechanistic aspects of muscle metabolism to the application of exercise to counteract dysfunction of metabolically-active tissues including liver and muscle itself.

KEY WORDS: Exercise, Fasting, Insulin Resistance, Lipid Metabolism

Das Bewusstsein,dass Bewegung ein wesentliches Mittel ist, um auf gesundheitliche Herausforderungen angemessen zu reagieren, nimmt weltweit zu. Obwohl der Ganzkörperstoffwechsel von vielen Organen gesteuert wird, welche kommunizieren, um die metabolische Homöostase zu bestimmen, ist vor allem der Skelettmuskel zentral für die Reaktion auf metabolische Veränderungen, da er der Hauptort der Glukoseaufnahme und -nutzung ist.

So gehen Stoffwechselerkrankungen, die auf einen schlechten Umgang mit Lipid/Glukose aufgrund von Überernährung und unzureichender körperlicher Aktivität zurückzuführen sind, oft auf eine muskelmetabolische Dysfunktion zurück und umgekehrt. Es gibt Hinweise darauf, dass der lokale Schilddrüsenhormonspiegel im Muskel entscheidend für die Reaktion auf Bewegung ist und dass metabolisch aktive Schilddrüsenhormone als mögliche Trainingsmimetika angesehen werden können.

Basierend auf Daten, die sowohl bei Nagetieren als auch beim Menschen gewonnen wurden, soll dieser Kurzüberblick aufzeigen, warum die metabolische Muskelintegrität als Reaktion auf Bewegung (zunehmend in Kombination mit eingeschränkter Ernährung untersucht) für die Gesundheit entscheidend ist. Neben den mechanistischen Aspekten des Muskelstoffwechsels dient körperliche Bewegung der Bekämpfung der Dysfunktion von stoffwechselaktiven Geweben einschließlich Leber und Muskel.

SCHLÜSSELWÖRTER: Bewegung, Fasten, Insulinresistenz, Fettstoffwechsel

Skeletal muscle can switch from lipid to carbohyd­rate use or vice versa depending on exercise inten­sity (see for review: (30)). These metabolic switches are reflected by changes in metabolic activity of either glycolytic muscle fibers (type IIb/type IIx) with resistance exercise (17, 24) or oxidative mu­scle fibers (type IIa and type I) with endurance exercise (24).

Both resistance and endurance exercise have be­neficial effects on muscle metabolism in rodents and humans, resulting in fat loss and increased insulin sensitivity (reviewed in: (22)). Metabolic changes during, and in response to, exercise which increase lipid oxidation occur in a variety of organs such as liver (11, 20, 27, 42) and white­(11, 14, 20, 30, 32) and brown adipose tissue (14, 25).

This results in an enhanced lipid clearance from the cir­culation in response to exercise and thus controls fat uptake in muscle. Exposure of muscle to a surplus of fat compromi­ses its metabolic activity (26), and thus one major physiolo­gical consequence of the action of the aforementioned me­tabolically active tissues is the optimization of the muscle’s energy metabolism, by preventing overload of fatty acids. This is of importance since skeletal muscle accounts for over 80% of insulin­dependent glucose uptake (8), which makes this tissue an important target in the treatment of diabetes type 2.

Fasting and exercise both induce fat loss, and may thus perhaps not be surprising that food deprivation causes metabolic shifts in skeletal muscle that partially overlap with exercise [see for review: (12)]. Food deprivation in ro­dent muscle results in activation of AMP activated protein kinase (AMPK) (3, 5, 10, 37, 45), considered to be an “energy sensor” (21).

Carbohydrate oxidation during food deprivation is sup­pressed by up­regulation of the Forkhead transcription factor FOXO1 (FKHR), inducing expression of pyruvate dehydrogenase kinase 4 (PDK4) (18). The subsequent PDK4­dependent phos­phorylation of the E1 component of the pyruvate dehydro­genase (PDH) complex causes downregulation of carbohydrate oxidation (36).

The central role for AMPK is further highlighted by the fact that during food deprivation a functional β2 subunit of AMPK in muscle has been shown to be crucial in preventing hypogly­cemia (5), and that in addition AMPK controls intramuscular glycogen breakdown in food­deprived muscle (3). Although one study performed in humans did not find direct evidence for a role of AMPK in the fasting­induced metabolic switch from carbohydrate to fat in muscle (43), a recent study in humans reported a 30% increase in AMPK phosphorylation upon fasting in muscle (34).

As opposed to fasting, during exercise in mice (progressive treadmill running test starting at 10 m/min upto maximum speed), AMPK has been shown to be essential for glucose uptake in the contracting muscle (31). Recent research has revealed the AMPK γ3 subunit to be crucial for greater Akt substrate of 160 kDa (AS160) phosphorylation at Ser 704, associated with increased glucose uptake in muscle after swimming for 4x30 min bouts, with 5 min rest period between each bout (41).

In response to both food deprivation and exercise, the AMPK pathway overlaps with those induced by the sirtuin SIRT1, a deacetylase that activates peroxisome proliferator activated receptor γcoactivator­1α(PGC­1α), inducing a gene expres­sion program governing the switch toward lipid catabolism (4). In the same study it has been shown that the action of SIRT1 depends on AMPK, since AMPK γ3 KO mice failed to induce SIRT1­dependent deacetylation of PGC­1α(4). PDH in­hibition also occurs during exercise in mice (treadmill run of 13 and 18 m.min−1) and is shown to depend of the AMPK α2 subunit (16).

Of note, it has been shown in mice that local thyroid hormo­ne 3,5,3’­triiodo­L­thyronine (T3) levels are crucial for the muscle’s response to exercise (1). Muscle­specific ablation of deiodinase 2, blocking local conversion of T4 into T3 within the myofiber, impaired acute exercise­induced PGC­1αex­pression, leading to muscle mitochondrial malfunction (1). In conjunction with this important observation, it has been shown in rats that thyroid hormones can be considered exer­cise mimetics (13, 29, 33) and that one metabolically active thyroid hormone, 3,5­diiodo­L­thyronine (3,5­T2), tones down fat­induced muscle­(29) and whole­body insulin resistance, in a SIRT1­dependent manner (9).

Skeletal muscle autophagy, induced both by fasting and exer­cise, is an essential process that ensures both muscle inte­grity and metabolic homeostasis. During food deprivation, autophagy in muscle fibers is necessary for proteolysis lea­ding to increased circulating levels of alanine, an essential amino acid required for gluconeogenesis thus preventing hypoglycemia.

Again, this process is under control of AMPK, since its mu­scle­specific ablation in mice results in a block of autophagy during food deprivation accompanied by reduced muscle mitochondrial function (3). Autophagy also occurs during exer­cise recovery in humans, during which it has been primarily linked to mitochondrial quality­control, and has been shown to be associated with increased phosphorylation of AMPK at Thr 172 as well as that of the autophagy marker UNC51­like kinase (ULK) at Ser 317 (2).

At the structural level, mechanically damaged cytoskeletal proteins in response to resistance exercise (75% to 80% of ma­ximum voluntary force) are degraded by Chaperone­assisted selective autophagy (CASA), a tension­induced degradation pathway, in order to ascertain muscle maintenance (38). The CASA complex is anchored at the Z­disk of the sarcomere by interacting with a protein termed actin­crosslinking protein FLNC (filamin C, gamma), and subsequently recognizes and acts on unfolding protein domains within the filamin rods du­ring contraction of the actin network (38). Given their common features, the effect of combinations of fasting and exercise on the autophagy­muscle repair process has been studied in ro­dents (45) and humans (15, 28, 39).

Surprisingly, in rodents, exercise (treadmill run at 12 m/min for 2h, with a 10° inclination) has been shown to suppress (24h) starvation­induced autophagy by reactivating mammalian target of rapamycin (mTOR) signaling including Akt, accom­panied by increased AMPK phosphorylation over starvation and exercise alone (45). This synergistic increase in AMPK phos­phorylation, accompanied by increased PDK4 transcription, has recently also been observed in humans after 15h of fasting and cycling for 1h at 70% Wmax.

In humans, a 6­week supervised training programme (3x/week, 60–120 min) in combination with fasting during training induces post­exercise reactivation of eukaryotic elongation fac­tor 2 (eEF2), and thus was suggested by the authors to facili­tate muscle repair by re­activation of protein translation (39). In apparent contrast, another human study showed that the autophagic signaling through Unc­51 like autophagy activating kinase 1 (ULK1) induced by exercise (a single bout of cycling exercise at 50% VO2max for 60 min or until fatigued, in concomitance with a continuous glucose infusion after an overnight fast (to mimic the pran­dial state) or following a 36­h fasting period) is not repressed by fasting (28).

However, a very recent study showed that in trained subjects (based on maximum oxygen uptake, muscle citrate synthase activity, and oxidative phos­phorylation protein level) the (36 h) fasting­induced autophagy through ULK1 was repressed (15), showing that combinations of both stimuli can indeed modu­late autophagy in humans.

It may be speculated that short­term repression of autophagy under these circumstances may increase muscle mass under specific training conditions, but further studies need to be performed to clarify this is­sue. A schematic overview of key metabolic and signa­ling events induced by fasting, (endurance) exercise, and their combination in skeletal muscle is depicted in Figure 1.

Given the metabolic impact of exercise, endurance training has been employed for the treatment of non­alcoholic fatty liver disease (NAFLD), with opti­mal training programs differing among individuals (see, for reviews: (35, 42)). In addition, recent stu­dies have shown that resistance training increases muscle GLUT4 activity, alleviates insulin resistance and ameliorates lipid profiles in patients with type 2 diabetes (6, 23).

Subjects with NAFLD have been shown to benefit from resistance exercise and show diminished in­trahepatic lipids, improved glucose tolerance, and a shift toward whole­body oxidative metabolism (20). Weight loss was not observed, and the authors sugge­sted combined therapy including caloric restriction, having known synergistic effects on metabolism com­bined with exercise in humans (7, 34, 39).

Importantly, diet compositions change the outcome: car­bohydrate­rich diets prior to or during exercise abolish the sti­mulatory effect of caloric restriction on exercise­induced fatty acid oxidative capacity (19). In this light, it is perhaps not sur­prising that the diet composition also influences training effec­tiveness (44). Based on these observations, in the Netherlands a program based on the combination of fasting and exercise is applied on healthy volunteers nationwide (40).

Basic and translational research has made considerable pro­gress in the understanding how exercise, in combination with fasting/caloric restriction, taking the dietary context into ac­count, can ameliorate the metabolic profile of muscle and the whole body to counteract metabolic disturbances including type 2 diabetes mellitus. This is of importance given the recent worldwide increase in the occurrence of obesity and its related complications.

Conflict of Interest
The authors have no conflict of interest.