Pharmacological inhibition of TLR4 ameliorates muscle and liver ceramide content after disuse in previously physically active mice.

Toll-like receptor 4 (TLR4) is a proposed mediator of ceramide accumulation, muscle atrophy, and insulin resistance in skeletal muscle. It is currently unknown whether pharmacological inhibition of TLR4, using the TLR4-specific inhibitor TAK-242 during muscle disuse, is able to prevent changes in intracellular ceramide species and consequently preserve muscle size and insulin sensitivity in physically active mice. To address this question, we subjected running wheel-conditioned C57BL/6 male mice (13 wk old; ∼10/group) to 7 days of hindlimb suspension (HS), 7 days of continued wheel running (WR), or daily injections of TAK-242 during HS (HS + TAK242) for 7 days. We measured hindlimb muscle morphology, intramuscular and liver ceramide content, HOMA-IR, mRNA proxies of ceramide turnover and lipid trafficking, and muscle fatty acid and glycerolipid content. As a result, soleus and liver ceramide abundance was greater (P < 0.05) in HS vs. WR but was reduced with TLR4 inhibition (HS + TAK-242 vs. HS). Muscle mass declined (P < 0.01) with HS (vs. WR), but TLR4 inhibition did not prevent this loss (soleus: P = 0.08; HS vs. HS + TAK-242). HOMA-IR was impaired (P < 0.01) in HS versus WR mice, but only fasting blood glucose was reduced with TLR4 inhibition (HS + TAK-242 vs HS, P < 0.05). Robust decreases in muscle Spt2 and Cd36 mRNA and muscle lipidomic trafficking may partially explain reductions in ceramides with TLR4 inhibition. In conclusion, pharmacological TLR4 inhibition in wheel-conditioned mice prevented ceramide accumulation during the early phase of hindlimb suspension (7 days) but had little effect on muscle size and insulin sensitivity.

Comparison of Varying Corticosteroid Type, Dose, and Volume for the Treatment of Pain in Small- and Intermediate-Size Joint Injections: A Narrative Review.

OBJECTIVE: To systematically evaluate the scientific literature examining the effect of corticosteroid type, dose, and volume of small- and intermediate-size joint injections on pain and function. TYPE: Narrative review. LITERATURE SURVEY: Medline (PubMed), Cochrane Central Register of Controlled Trial, and SportDiscus databases were searched. METHODOLOGY: Inclusion criteria included prospective studies evaluating pain- and/or function-related improvements following a corticosteroid injection of a small- or intermediate-size joint. SYNTHESIS: A total of 28 articles were included, all studying patients with osteoarthritis and/or rheumatoid arthritis. Eleven studies were randomized-controlled trials comparing corticosteroid injections to a control treatment and three were randomized trials comparing corticosteroid dose or type; the rest were prospective case series without a control. Most studies used 10 to 20 mg of methylprednisolone or triamcinolone for small joints and 20 to 40 mg for intermediate joints; wrist joints were the only joint studied that directly compared doses-20 mg was noninferior to 40 mg. Triamcinolone hexacetonide was found to be superior to methylprednisolone in the interphalangeal finger joints in a single randomized-controlled trial; no other studies compared steroid types in any joint. No studies evaluated the effect of volume on clinical outcomes. CONCLUSIONS: Very few studies directly examine the effect of corticosteroid type, corticosteroid dose, or injectate volume on clinical outcomes for small- or intermediate-size joint arthralgia. Future studies are needed to better elucidate the most effective treatment protocols. LEVEL OF EVIDENCE: IV.