Statin-associated changes in skeletal muscle function and stress response after novel or accustomed exercise.

INTRODUCTION: The most common side effect of statins, myopathy, is more likely in exercisers. We investigated the interaction of statin treatment with novel vs. accustomed exercise on muscle function, heat shock protein (Hsp) expression, and caspase activation. METHODS: Mice received daily cerivastatin or saline for 2 weeks, with/without wheel running (RW) (novel/sedentary). Accustomed groups completed 2 weeks of RW before statins. At 4 weeks, plantarflexor isometric force, Hsp25, αB-crystallin, caspase-3 and -9, and plasma creatine kinase (CK) were quantified. RESULTS: Statins reduced force in sedentary and novel groups, compared with saline, by 15% and 27%, respectively. Muscle fatigability increased 21% and 30% with statins compared with saline in sedentary and novel groups, respectively. Accustomed exercise prevented statin-associated force loss and increased fatigability. CK did not correlate with functional outcomes. RW increased Hsp protein in all groups. CONCLUSION: Our results suggest that exercise prior to statin treatment can protect against decrements in muscle function.

The Associations between Physical Fitness, Complex vs Simple Movement, and Academic Achievement in a Cohort of Fourth Graders.

This study analyzed the correlation between elementary school students' body composition, physical activity, physical fitness, movement ability, and academic achievement. Movements ranged from simple actions to complex movements requiring executive functioning. In total, 110 fourth graders (60 boys, 50 girls) participated in this experiment. Body composition (BMI, % of body fat), physical activity (pedometer), physical fitness (muscular strength, endurance, power, flexibility, and VO2max), and complex movement abilities (Illinois Agility test, soda pop hand test, and soda pop foot test) were measured. Regression modeling of body composition and fitness/activity variables was able to account for 30.5% of the variation of total academic scores in females, but only 4.3% in males. No individual tests were reliably correlated with multiple academic outcomes in males. However, hand and foot soda pop times, as well as Illinois Agility scores, were repeatedly correlated with academic outcomes in females, each correlating with 4 of the 6 academic scores. Body composition and physical activity level did not correlate with academic achievement, and simple physical fitness showed a low correlation with academic achievement in both boys and girls. On the other hand, complex, cognitively demanding movements such as the Illinois Agility, soda pop hand, and soda pop foot tests had consistent correlations with academic achievement in girls, but not in boys.

Statin-associated myopathy and its exacerbation with exercise.

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are a common and effective treatment for hypercholesterolemia, with a low overall rate of side-effects. The most common complication is some degree of skeletal muscle myopathy, ranging from painless serum creatine kinase elevations to rhabdomyolysis. Unfortunately, the likelihood and/or severity of complications increases with the combination of statin treatment and physical activity. The specific pathways that mediate statin-associated myopathy are unclear, and research directly addressing the exacerbation with exercise is limited. Potential mechanisms include the induction of skeletal muscle fiber apoptosis, alterations in ubiquitin-proteasome pathway activity, mitochondrial dysfunction, and terpenoid depletion. In this review we provide an overview of research that specifically addresses the combination of statin-associated myopathy and physical activity and highlight some deficiencies in the available literature, as well as future directions for this important subset of statin-associated myopathy.

Glutamine preserves skeletal muscle force during an inflammatory insult.

The purpose of this study was to test the hypothesis that acute glutamine (GLN) supplementation can counteract skeletal muscle contractile dysfunction occurring in response to inflammation by elevating muscle heat shock protein (Hsp) expression and reducing inflammatory cytokines. Mice received 5 mg/kg lipopolysaccharide (LPS) concurrently with 1 g/kg GLN or vehicle treatments. Plantarflexor isometric force production was measured at 2 hours post-injection. Blood and gastrocnemius muscles were collected, and serum and muscle tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) and muscle Hsp70 and Hsp25 were quantified. Saline/LPS treatment was associated with a 33% reduction in maximal force and elevated serum TNF-alpha and IL-6. GLN completely prevented this force decrement with LPS. GLN was found to reduce muscle Hsp70 and IL-6, but only in the presence of LPS. GLN supplementation provides an effective, novel, clinically applicable means of preserving muscle force during acute inflammation. These data indicate that force preservation is not dependent on reductions in serum cytokines or muscle TNF-alpha, or elevated Hsp levels.

Contribution of IL-6 to the Hsp72, Hsp25, and alphaB-crystallin [corrected] responses to inflammation and exercise training in mouse skeletal and cardiac muscle.

The heat shock proteins (Hsps) Hsp72, Hsp25, and alphaB-crystallin (alphaB C) [corrected]may protect tissues during exercise and/or inflammatory insults; however, no studies have investigated whether exercise training increases both basal and inflammation-induced expression of these Hsps in skeletal or cardiac muscle. IL-6 is produced by muscle during both exercise and inflammation and has been shown to modulate Hsp expression. These studies tested the hypothesis that voluntary wheel running (RW) increases basal and inflammation-induced Hsp72, Hsp25, and alphaB C [corrected] protein through an IL-6-dependent mechanism. We compared Hsp72, Hsp25, alphaB C, [corrected] and IL-6 protein levels 4 h after systemic inflammation induced by lipopolysaccharide (LPS) in skeletal and cardiac muscles of wild-type (IL-6(+/+)) and IL-6 deficient (IL-6(-/-)) mice after 2 wk of RW or normal cage activity (Sed). LPS significantly increased skeletal Hsp72 and Hsp25 relative to saline in Sed IL-6(+/+), but not IL-6(-/-) mice. LPS increased Hsp72 relative to saline in Sed IL-6(+/+) cardiac muscle. RW increased basal Hsp72, Hsp25, and alphaB C [corrected] in skeletal muscle in IL-6(+/+) and IL-6(-/-) mice. However, LPS was not associated with increases in any Hsp in RW IL-6(+/+) or IL-6(-/-) mice. LPS increased IL-6 protein in skeletal muscle and plasma in Sed and RW groups, with a significantly greater response in RW. The major results provide the first in vivo evidence that the absence of IL-6 is associated with reduced skeletal muscle Hsp72 and Hsp25 responses to LPS, but that IL-6 is not required for exercise-induced Hsp upregulation in skeletal or cardiac muscle.

The Impact of Exercise on Statin-Associated Skeletal Muscle Myopathy.

HMG-CoA reductase inhibitors (statins) are the most effective pharmacological means of reducing cardiovascular disease risk. The most common side effect of statin use is skeletal muscle myopathy, which may be exacerbated by exercise. Hypercholesterolemia and training status are factors that are rarely considered in the progression of myopathy. The purpose of this study was to determine the extent to which acute and chronic exercise can influence statin-induced myopathy in hypercholesterolemic (ApoE-/-) mice. Mice either received daily injections of saline or simvastatin (20 mg/kg) while: 1) remaining sedentary (Sed), 2) engaging in daily exercise for two weeks (novel, Nov), or 3) engaging in daily exercise for two weeks after a brief period of training (accustomed, Acct) (2x3 design, n = 60). Cholesterol, activity, strength, and indices of myofiber damage and atrophy were assessed. Running wheel activity declined in both exercise groups receiving statins (statin x time interaction, p<0.05). Cholesterol, grip strength, and maximal isometric force were significantly lower in all groups following statin treatment (statin main effect, p<0.05). Mitochondrial content and myofiber size were increased and 4-HNE was decreased by exercise (statin x exercise interaction, p<0.05), and these beneficial effects were abrogated by statin treatment. Exercise (Acct and Nov) increased atrogin-1 mRNA in combination with statin treatment, yet enhanced fiber damage or atrophy was not observed. The results from this study suggest that exercise (Nov, Acct) does not exacerbate statin-induced myopathy in ApoE-/- mice, yet statin treatment reduces activity in a manner that prevents muscle from mounting a beneficial adaptive response to training.

The α7ß1-integrin increases muscle hypertrophy following multiple bouts of eccentric exercise.

Mechanical stimuli increase skeletal muscle growth in a mammalian target of rapamycin (mTOR)- and p70(S6K)-dependent manner. It has been proposed that costameric proteins at Z bands may sense and transfer tension to these initiators of protein translation, but few candidates have been identified. The purpose of this study was to determine whether a role exists for the α(7)-integrin in the activation of hypertrophic signaling and growth following eccentric exercise training. Five-week-old, wild-type (WT) and α(7)BX2-integrin transgenic (α(7)Tg) mice were randomly assigned to one of two groups: 1) sedentary (SED), or 2) exercise training (EX). Exercise training consisted of downhill running 3 sessions/wk for 4 wk (-20°, 17 m/min, 30 min). Downhill running was used to induce physiological mechanical strain. Twenty-four hours following the final training session, maximal isometric hindlimb plantar flexor force was measured. Gastrocnemius-soleus complexes were collected for further analysis of signaling changes, which included AKT, mTOR and p70(S6K), and muscle growth. Despite increased p70(S6K) activity in WT/EX, no significant changes in cross-sectional area or force were observed in WT/EX compared with WT/SED. AKT, mTOR, and p70(S6K) activation was higher, and whole muscle hypertrophy, relative muscle weight, myofibrillar protein, and force were significantly elevated in α(7)Tg/EX compared with α(7)Tg/SED. A marked increase in average myofiber cross-sectional area was observed in α(7)Tg/EX compared with all groups. Our findings demonstrate that the α(7)ß(1)-integrin sensitizes skeletal muscle to mechanical strain and subsequent growth. Thus the α(7)ß(1)-integrin may represent a novel molecular therapy for the treatment of disuse muscle atrophy.