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.

The α(7)β(1)-integrin is a heterodimeric transmembrane protein that adheres to laminin in the extracellular matrix, representing a critical link that maintains structure in skeletal muscle. In addition to preventing exercise-induced skeletal muscle injury, the α(7)-integrin has been proposed to act as an intrinsic mechanosensor, initiating cellular growth in response to mechanical strain. The purpose of this study was to determine the extent to which the α(7)-integrin regulates muscle hypertrophy following eccentric exercise. Wild-type (WT) and α(7)-integrin transgenic (α(7)Tg) mice completed a single bout of downhill running exercise (-20°, 17 m/min, 60 min), and gastrocnemius-soleus complexes were collected 1, 2, 4, and 7 days (D) postexercise (PE). Maximal isometric force was maintained and macrophage accumulation was suppressed in α(7)Tg muscle 1D PE. Mean fiber cross-sectional area was unaltered in WT mice but increased 40% in α(7)Tg mice 7D PE. In addition, a rapid and striking fivefold increase in embryonic myosin heavy chain-positive fibers appeared in α(7)Tg mice 2D PE. Although Pax7-positive satellite cells were increased in α(7)Tg muscle 1D PE, the number of nuclei per myofiber was not altered 7D PE. Phosphorylation of mammalian target of rapamycin (mTOR) was significantly elevated in α(7)Tg 1D PE. This study provides the first demonstration that the presence of the α(7)β(1)-integrin in skeletal muscle increases fiber hypertrophy and new fiber synthesis in the early time course following a single bout of eccentric exercise. Further studies are necessary to elucidate the precise mechanism by which the α(7)-integrin can enhance muscle hypertrophy following 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)β(1)-integrin sensitizes skeletal muscle to mechanical strain and subsequent growth. Thus the α(7)β(1)-integrin may represent a novel molecular therapy for the treatment of disuse muscle atrophy.

Exaggerated proinflammatory cytokine responses can be observed with aging, and reduced levels of the anti-inflammatory cytokine IL-10 may contribute to these responses. IL-10 can reduce IL-6, IL-1beta, and TNF-alpha expression in nonmuscle tissues; however, no studies have examined the combined effects of IL-10 and age on cytokine responses in skeletal and cardiac muscle. These experiments tested the hypothesis that the absence of IL-10, in vivo, is associated with greater IL-6, TNF-alpha, and IL-1beta responses to an inflammatory challenge in skeletal and cardiac muscle and that aging exaggerates these responses. We compared IL-6, IL-1beta, and TNF-alpha mRNA and protein levels in skeletal and cardiac muscle of young (4 mo) and mature (10-11 mo) wild-type (IL-10(+/+)) and IL-10 deficient (IL-10(-/-)) mice following LPS. Skeletal and cardiac IL-6 mRNA and protein were elevated by LPS for IL-10(+/+) and IL-10(-/-) mice with greater responses in the IL-10(-/-) mice (P < 0.01). In skeletal muscle these effects were greater in mature than young mice (P < 0.01). IL-1beta mRNA and protein responses to LPS were greater in cardiac muscle of young but not mature IL-10(-/-) mice compared with IL-10(+/+) (P < 0.01). However, IL-1beta responses were greater in mature than young mice, but only in IL-10(+/+) groups (P < 0.05). The absence of IL-10 was associated with higher TNF-alpha protein levels in cardiac muscle (P < 0.05). The results provide the first in vivo evidence that the absence of IL-10 is associated with a greater IL-6 response to LPS in skeletal and cardiac muscles, and in skeletal muscle aging further exaggerates these responses.

Huey KA, Meador BM. Contribution of IL-6 to the Hsp72, Hsp25, and ␣␤-crystallin responses to inflammation and exercise training in mouse skeletal and cardiac muscle.