Metabolic effects of α-lipoic acid supplementation in pre-diabetics: a randomized, placebo-controlled pilot study.

Supplementation of health promoting nutraceuticals may be an effective adjunct strategy with other lifestyle and drug approaches to impede disease progression in prediabetic subjects. α-Lipoic acid, a naturally occurring short-chain fatty acid, has been extensively evaluated for its antioxidant and glycemic control properties but has rarely been investigated as a lipid-lowering strategy. We conducted a pilot study to examine the effects of α-lipoic acid supplementation on glycemic control and lipid profile in pre-diabetic, overweight/obese adults. The study was designed as a free-living, randomized, two-phase, placebo-controlled cross-over study with 12 pre-diabetic, dyslipidemic subjects. Eligible subjects completed two thirty-day phases (in random order) consisting of a placebo (600 mg cellulose per day) and α-lipoic acid treatment (600 mg day-1). Although no change (p < 0.05) in serum glucose was observed, α-lipoic acid-supplemented subjects demonstrated reduced fasting serum insulin (p = 0.04) and HOMA-IR (p = 0.07) compared with the placebo group. However, no change (p > 0.05) in serum lipids (including total cholesterol, LDL-C, HDL-C, triglycerides, LDL-C/HDL-C, and TC/HDL-C) were observed. Study results suggest that α-lipoic acid supplementation may be a useful strategy to improve insulin sensitivity in pre-diabetic subjects but is not effective in modulating serum lipids.

Effect of an Acute Bout of Kettlebell Exercise on Glucose Tolerance in Sedentary Men: A Preliminary Study.

Impaired glucose tolerance can have significant health consequences. The purposes of this preliminary study were to examine whether a single session of kettlebell exercise improves acute post-exercise glucose tolerance in sedentary individuals, and whether it was as effective as high-intensity interval running. Six sedentary male subjects underwent a two-hour oral glucose tolerance test following three different conditions: 1) control (no exercise); 2) kettlebell exercise (2 sets of 7 exercises, 15 repetitions per exercise with 30 seconds rest between each exercise); or 3) high-intensity interval running (10 one-minute intervals at a workload corresponding to 90% VO2max interspersed with one-minute active recovery periods). Blood glucose and insulin levels were measured before (0 minutes), and 60 and 120 minutes after glucose ingestion. Both kettlebell and high-intensity interval running exercise significantly lowered blood glucose 60 minutes after glucose ingestion compared with control. However, there was no significant difference in blood glucose between the two exercise conditions at any time point. In addition, there were no significant differences in insulin concentration between high intensity interval running, kettlebell, and control conditions at all time points. Results indicate that an acute bout of kettlebell exercise is as effective as high intensity interval running at improving glucose tolerance in sedentary young men.

Metabolic response of different high-intensity aerobic interval exercise protocols.

Although high-intensity sprint interval training (SIT) employing the Wingate protocol results in significant physiological adaptations, it is conducted at supramaximal intensity and is potentially unsafe for sedentary middle-aged adults. We therefore evaluated the metabolic and cardiovascular response in healthy young individuals performing 4 high-intensity (~90% VO2max) aerobic interval training (HIT) protocols with similar total work output but different work-to-rest ratio. Eight young physically active subjects participated in 5 different bouts of exercise over a 3-week period. Protocol 1 consisted of 20-minute continuous exercise at approximately 70% of VO2max, whereas protocols 2-5 were interval based with a work-active rest duration (in seconds) of 30/30, 60/30, 90/30, and 60/60, respectively. Each interval protocol resulted in approximately 10 minutes of exercise at a workload corresponding to approximately 90% VO2max, but differed in the total rest duration. The 90/30 HIT protocol resulted in the highest VO2, HR, rating of perceived exertion, and blood lactate, whereas the 30/30 protocol resulted in the lowest of these parameters. The total caloric energy expenditure was lowest in the 90/30 and 60/30 protocols (~150 kcal), whereas the other 3 protocols did not differ (~195 kcal) from one another. The immediate postexercise blood pressure response was similar across all the protocols. These finding indicate that HIT performed at approximately 90% of VO2max is no more physiologically taxing than is steady-state exercise conducted at 70% VO2max, but the response during HIT is influenced by the work-to-rest ratio. This interval protocol may be used as an alternative approach to steady-state exercise training but with less time commitment.

Ageing prolongs inflammatory marker expression in regenerating rat skeletal muscles after injury.

BACKGROUND: Some of the most serious consequences of normal ageing relate to its effects on skeletal muscle, particularly significant wasting and associated weakness, termed "sarcopenia". The underlying mechanisms of sarcopenia have yet to be elucidated completely but an altered muscle inflammatory response after injury is a likely contributing factor. In this study we investigated age-related changes in the expression of numerous inflammatory markers linked to successful muscle regeneration. METHODS: Right extensor digitorum longus (EDL) muscles from young (3 month), adult (12 month) and old (24 month) male F344 rats were injected with bupivacaine hydrochloride to cause complete muscle fibre degeneration, then excised 12, 24, 36, and 72 hours later (n = 5/age group/time point). We used qRT-PCR to quantify the mRNA expression levels of the inflammatory markers TNFα, IFNγ, IL1, IL18, IL6, and CD18 as well as regenerative markers MyoD and myogenin. RESULTS: Inflammatory markers were all increased significantly in all age groups after myotoxic injury. There was a trend for expression of inflammatory markers to be higher in uninjured muscles of old rats, especially at 72 hours post injury where the expression levels of several markers was significantly higher in old compared with young and adult rats. There was also a decrease in the expression of regenerative markers in old rats at 72 hours post injury. CONCLUSION: Our findings identify a prolonged inflammatory signature in injured muscles from old compared with young and adult rats together with a blunted expression of key markers of regeneration in muscles of old rats. Importantly, our findings identify potential targets for future therapeutic strategies for improving the regenerative capacity of skeletal muscle during ageing.

Episodic hypoxia exacerbates respiratory muscle dysfunction in DMD(mdx) mice.

Many patients with Duchenne muscular dystrophy (DMD) are eventually diagnosed with sleep-disordered breathing (SDB). SDB is associated with reduced ventilation, decreased arterial oxygen tension, and increased respiratory muscle recruitment during sleep, factors that could be especially detrimental to respiratory muscles in DMD. To assess whether SDB impacts dystrophin-deficient respiratory muscle function and fibrosis, diaphragm strength, and collagen content were evaluated in dystrophic mice (Dmd(mdx)) exposed to experimental SDB. Diurnal exposure to episodic hypoxia resulted in a 30% reduction in diaphragm strength without affecting collagen content. Episodic hypoxia secondary to SDB can exacerbate respiratory muscle dysfunction in DMD.

Intermittent hypoxia reduces upper airway stability in lean but not obese Zucker rats.

Obstructive sleep apnea involves intermittent periods of airway occlusions that lead to repetitive oxygen desaturations. Exposure to chronic intermittent hypoxia (IH) in rats increases diurnal blood pressure and alters skeletal muscle physiology. The impact of IH on upper airway muscle function is unknown. We hypothesize that IH exposure increases upper airway collapsibility in rats due to alterations of the muscles surrounding the upper airway. Lean and obese rats were exposed to cyclic alterations in O(2) levels (20.6%-5%) every 90 s, 8 h/day for 6 days/wk for 12 wk. Following the exposure period, arterial pressure was recorded via the tail artery in conscious unrestrained rats. Mean arterial pressure was increased in lean IH but not in obese IH-exposed Zucker rats (P < 0.05). The pharyngeal pressure associated with airway collapse (P(crit)) was measured under anesthesia during baseline conditions and then during supramaximal stimulation of the hypoglossal nerve (cnXII). Baseline P(crit) was more positive (more collapsible) in lean but not obese rats following 12 wk of IH (P < 0.05), while supramaximal stimulation of cnXII increased airway stability (decreased P(crit)) in both lean and obese Zucker rats following IH to levels that were similar to their respective room air controls. The in vitro peak tension and the expression of the individual myosin heavy chain isoforms from the upper airway muscles were unaltered following IH. We conclude that IH leads to increases in baseline collapsibility in lean Zucker rats exposed to IH by nonmyogenic mechanisms.

A comparison of factors associated with collagen metabolism in different skeletal muscles from dystrophic (mdx) mice: impact of pirfenidone.

Skeletal muscles in mdx mice exhibit differential degrees of pathological changes and fibrosis. The purpose of this study was to examine differences in various indices of collagen metabolism in skeletal muscles with widely different functions and activity profiles in mdx mice, and to determine whether pirfenidone would attenuate the development of fibrosis. Mice in the pirfenidone group were orally fed pirfenidone (500 mg/kg) daily for 4 weeks. Marked differences were noted in hydroxyproline concentration between muscles, which could not be explained solely by the level of type I collagen and transforming growth factor-beta1 (TGF-beta1) mRNA. In normal mice, matrix metalloproteinase (MMP)-2 mRNA was significantly higher in the gastrocnemius than in the diaphragm or genioglossus muscles, suggesting that collagen degradation plays an important role in regulating collagen accretion in skeletal muscle. In mdx mice, the levels of both MMP-2 and MMP-9 mRNA were significantly elevated relative to control, although the response was muscle specific. Pirfenidone treatment resulted in a significant reduction in the level of hydroxyproline concentration across all muscles, although the effect was small. Results from this study reveal intrinsic dissimilarities in collagen metabolism between functionally different skeletal muscles. Moreover, the pharmacological use of pirfenidone may be beneficial in preventing fibrosis in muscular dystrophy.

Respiratory muscle training improves swimming endurance in divers.

Respiratory muscles can fatigue during prolonged and maximal exercise, thus reducing performance. The respiratory system is challenged during underwater exercise due to increased hydrostatic pressure and breathing resistance. The purpose of this study was to determine if two different respiratory muscle training protocols enhance respiratory function and swimming performance in divers. Thirty male subjects (23.4 +/- 4.3 years) participated. They were randomized to a placebo (PRMT), endurance (ERMT), or resistance respiratory muscle training (RRMT) protocol. Training sessions were 30 min/day, 5 days/week, for 4 weeks. PRMT consisted of 10-s breath-holds once/minute, ERMT consisted of isocapnic hyperpnea, and RRMT consisted of a vital capacity maneuver against 50 cm H(2)O resistance every 30 s. The PRMT group had no significant changes in any measured variable. Underwater and surface endurance swim time to exhaustion significantly increased after RRMT (66%, P < 0.001; 33%, P = 0.003) and ERMT (26%, P = 0.038; 38%, P < 0.001). Breathing frequency (f (b)) during the underwater endurance swim decreased in RRMT (23%, P = 0.034) and tidal volume (V (T)) increased in both the RRMT (12%, P = 0.004) and ERMT (7%, P = 0.027) groups. Respiratory endurance increased in ERMT (216.7%) and RRMT (30.7%). Maximal inspiratory and expiratory pressures increased following RRMT (12%, P = 0.015, and 15%, P = 0.011, respectively). Results from this study indicate that respiratory muscle fatigue is a limiting factor for underwater swimming performance, and that targeted respiratory muscle training (RRMT > ERMT) improves respiratory muscle and underwater swimming performance.

Pentoxifylline fails to attenuate fibrosis in dystrophic (mdx) diaphragm muscle.

Fibrosis is a common pathological feature observed in muscle from patients with Duchenne muscular dystrophy and in mdx diaphragm. The purpose of this study was to determine whether pentoxifylline (PTX) treatment for 4 weeks (16 mg/kg/day) could significantly attenuate the process of fibrosis in diaphragm muscle from mdx mice. PTX treatment had no impact on in vitro diaphragm muscle contractile function. In addition, diaphragm muscle hydroxyproline concentration and the level of type I and III collagen and TGF-beta1 mRNA were unaffected by PTX treatment. These findings do not support the use of PTX as an antifibrotic drug for the treatment of muscular dystrophy.

Localization and early time course of TGF-beta 1 mRNA expression in dystrophic muscle.

Fibrosis is a common pathological feature observed in muscle from patients with Duchenne muscular dystrophy (DMD). In the dystrophic (mdx) mouse model of DMD, the diaphragm is more severely affected than other skeletal muscles. The level of transforming growth factor-beta1 (TGF-beta1), an inflammatory cytokine, is significantly elevated in mdx diaphragm. However, little is known about the onset of TGF-beta1 messenger ribonucleic acid (mRNA) expression, or which cells express the mRNA. In this study, we characterized the location and time course of expression of TGF-beta1 mRNA in diaphragm from mdx mice. TGF-beta1 mRNA was significantly elevated in mdx diaphragm at 6 and 9 but not 12 weeks of age, and these changes corresponded with changes in type I collagen mRNA and hydroxyproline concentration. Mononucleated cells localized to areas of fiber necrosis highly expressed the TGF-beta1 transcript in mdx diaphragm. Neutralization of TGF-beta1 by decorin administration resulted in a 40% reduction in the level of diaphragm muscle type I collagen mRNA. These findings support a role for TGF-beta1 during the early stages of fibrogenesis in dystrophic diaphragm muscle. Therapeutic interventions aimed at neutralizing this cytokine may be beneficial in slowing the development of fibrosis in DMD.

Effects of ovariectomy and estrogen on skeletal muscle function in growing rats.

This study examined the effect of estrogen replacement on soleus muscle size and contractile function in ovariectomized rats during physiological growth. Seven week old female Sprague-Dawley rats were assigned to one of three treatment groups: (1) control animals (SHAM), (2) ovariectomized animals without estrogen replacement (OVX/CO), and (3) ovariectomized animals with 17 beta-estradiol replacement (OVX/E2). OVX/CO and OVX/E2 animals were pair-fed to SHAM animals to rule out the potentially confounding effect of differences in food intake. Rats were sacrificed 4 weeks after surgery and the soleus muscle was removed for analysis. Estrogen replacement reduced body weight, relative body weight gain, and soleus muscle fiber size despite all groups having a similar food intake. Ovariectomy alone had no effect on any of these parameters suggesting that estrogen may inhibit skeletal muscle growth when it is the only ovarian hormone present. Neither ovariectomy nor estrogen replacement affected maximal specific isometric force. Estrogen replacement increased half relaxation time. Ovariectomy resulted in a reduction in time to peak tension that was reversed with estrogen replacement. This reduction was not accompanied by a change in myosin heavy chain composition implying that calcium handling may have been altered. Results from this study suggest that estrogen affects skeletal muscle growth and twitch kinetics.

Targeting the immune system to improve ventilatory function in muscular dystrophy.

Skeletal muscle is a unique tissue whose function is dependent in great part on its ultrastructure. Repeated intense muscular contractions, especially those resulting in muscle lengthening, can lead to alterations in muscle structure (i.e., muscle damage) and subsequent decline in contractile force. The damage-induced decline in contractile force can have a significant impact on exercise performance during an athletic performance. In some disease conditions such as Duchenne muscular dystrophy (DMD), the muscles are more vulnerable to contraction-induced damage than normal muscle. In the case of the respiratory muscles, for example, the diaphragm, the consequences of muscle weakness secondary to damage are profound in that respiratory failure leading to premature death often ensues. In normal skeletal muscle, damage is followed by an inflammatory response involving multiple cell types that subsides after several days. This transient inflammatory response is a normal homeostatic reaction to muscle damage. In contrast, a persistent inflammatory response is observed in dystrophic skeletal muscle that leads to an altered extracellular environment, including an increased presence of inflammatory cells (e.g., macrophages) and elevated levels of various inflammatory cytokines (e.g., TNF-alpha, TGF-beta). The signals that lead to successful muscle repair in healthy muscle may promote muscle wasting and fibrosis in dystrophic muscle. Preliminary data indicate that immunosuppression in dystrophic (mdx) mice has beneficial effects on some indices of muscle dysfunction, thereby indicating that targeted immunosuppression may offer some promise in delaying the pathological progression of this insidious muscular disease.

Ventilatory dysfunction in mdx mice: impact of tumor necrosis factor-alpha deletion.

Muscular dystrophy is associated with inflammation and fiber necrosis in the diaphragm that may alter ventilatory function. The purpose of this study was to determine to what extent in vivo ventilatory function in dystrophic (mdx) mice was compromised and to assess the impact of deletion of tumor necrosis factor-alpha (TNF-alpha), a known proinflammatory cytokine, on ventilatory function, diaphragm contractility, and myosin heavy chain (MHC) distribution in 10-12-month-old mdx mice. Although the resting ventilatory pattern did not significantly differ between control and mdx mice, the ventilatory response to hypercapnia in mdx mice was significantly attenuated. Elimination of TNF-alpha significantly improved the hypercapnic ventilatory response and diaphragm muscle maximal isometric force. Long-term TNF-alpha deletion also altered the myosin heavy chain isoform profile of the diaphragm. These data indicate that a blunted ventilatory response to hypercapnia exists in mdx mice, and that TNF-alpha influences the progressive deterioration of diaphragm muscle in mdx mice.

Impact of initial muscle length on force deficit following lengthening contractions in mammalian skeletal muscle.

The purpose of this study was to determine whether initial muscle length influenced the extent of isometric force deficit following 20 in vitro lengthening contractions of the soleus muscle from Fischer 344 rats. Force deficit was evaluated following one of five protocols: (1) lengthening contractions from optimal muscle length (Lo) to 120% Lo; (2) lengthening contractions from 80% Lo to Lo; (3) lengthening contractions from Lo to 120% Lo but with a stimulation frequency that elicited the same force as protocol 2; (4) 20 isometric contractions at Lo; (5) 20 stretches +/- 20% Lo in inactive muscle. Following lengthening contractions, extent of force deficit significantly differed between protocols 1, 2, and 3 (P < 0.05). Maximal isometric force (Po) was decreased by approximately 32%, approximately 8%, and approximately 15% in protocols 1, 2, and 3, respectively. In contrast, neither isometric contractions nor passive stretching (protocols 4 and 5) resulted in any reduction in Po. Irrespective of muscle length, the extent of force deficit was highly correlated (R = -0.774, P < 0.001) with peak force during active lengthening. Thus, the magnitude of isometric force deficit following lengthening contractions is influenced by both initial muscle length and peak force development. These findings have important practical implications for both exercise conditioning and rehabilitation, which are discussed.

Impact of endurance concentric contraction training on acute force deficit following in vitro lengthening contractions.

The purposes of this study were to (1) determine whether endurance training employing solely concentric contractions would reduce force deficit following lengthening contractions, and (2) to determine if aged skeletal muscle would respond similarly from training, compared with young animals. Young (3-month) and old (23-month) male Fischer 344 rats were randomly assigned to either a control or an exercise training group. Exercise training consisted of 10 weeks of treadmill running (15% grade, 45 min/day, and 5 days/week) such that by the end of training the young and old rats were exercising at 27 and 15 m/min, respectively (approximately 70% ). After training, the percent decrease in maximal isometric force ( P(o)) of the diaphragm muscle was measured in vitro at 26 degrees C immediately after a series of 20 lengthening contractions (20% strain from optimal muscle length, one contraction every 5 s), and at 5 and 10 min post-injury. At 10 min post-injury, P(o) averaged approximately 66% of initial P(o) in the exercise group (young and old combined) and approximately 61% of initial P(o) in the control groups (young and old combined) ( P<0.05). This difference represents an attenuation of force deficit by approximately 13% in the trained animals, compared with controls. These findings indicate that 10 weeks of endurance training employing solely concentric contractions is beneficial in minimizing acute force deficit after a bout of lengthening contractions in both young and old rats.

Diaphragm plasticity following intrinsic laryngeal muscle denervation in rats.

PURPOSE: During inspiration, recruitment of the intrinsic laryngeal muscles (ILM) reduces the inspiratory load on the ventilatory pump muscles. The purpose of our study was to determine 1) whether the diaphragm adapts to denervation of the ILM, and 2) whether the additional stimulus of exercise training affects the degree to which the diaphragm adapts to ILM denervation. METHODS: Thirty-six male Sprague-Dawley rats (2 months) were randomly divided into sedentary control (SC), sedentary-denervated (SD), and exercise-denervated (ED) groups. Control animals underwent sham operations, whereas ILM-denervated animals underwent bilateral transection of the recurrent laryngeal nerves. Three weeks after surgery, animals in the ED group performed a treadmill training protocol for a period of 6 wk. RESULTS: Denervation (SD and ED animals) of the ILM significantly increased diaphragm citrate synthase activity (20%), in vitro endurance, and time to peak twitch tension (15%), and reduced (13%) peak tetanic tension (Po, N x cm(-2)). No independent training effect over and above the effects attributed to denervation of ILM were noted in ED animals. CONCLUSION: The results highlight the role of vocal cord dilator function during both eupnea and exercise-induced hyperpnea.