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Heavily stressed muscles responded to massage therapy with a variety of biologic changes associated with reduced inflammation, analysis of tissue specimens showed.

Serial quadriceps-muscle biopsies showed reduced production of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin-6 (IL-6) following massage treatment of exercise-induced muscle damage.

Massage also was associated with activation of signaling pathways involved in stretch response and mitochondrial biogenesis, as reported online in Science Translational Medicine.

"Our findings suggest that the perceived positive effects of massage are a result of an attenuated production of inflammatory cytokines, which may reduce pain by the same mechanism as conventional anti-inflammatory drugs such as NSAIDs," according to Mark A. Tarnopolsky, MD, PhD, of McMaster University in Hamilton, Ontario, and colleagues.

"These results elucidate the biological effects of massage in skeletal muscle and provide evidence that manipulative therapies may be justifiable in medical practice."

The role of complementary and alternative medicine, including massage therapy, has expanded greatly as an adjunct to conventional medical practice. For many of the techniques, however, there is limited evidence regarding cellular or mechanistic effects to support their clinical use, the authors wrote in their introduction.

Massage therapy has been widely used as an aid to reduce pain and promote recovery of injured muscles. Hypothesized effects of massage have included moderation of inflammation, improved blood flow, and reduced tissue stiffness, all contributing to pain reduction, the authors continued.

The functional benefits of massage have remained unclear and controversial. Experiments in preclinical models have limited applicability because of their failure to mimic human responses. Despite reported long-term benefits of massage in chronic pain and range of motion, the biologic basis has eluded explanation.

To pin down the biologic effects of massage, Tarnopolsky and colleagues recruited 11 healthy male volunteers for a clinical study.

Each participant completed a standardized 15-minute period of intense exercise. Immediately after completing the exercise, participants received 10 minutes of massage for one leg and no treatment for the other leg.

Investigators obtained specimens of participants' quadriceps at rest, immediately after massage, and after a 2.5-hour recovery period.

Using whole-genome microarrays, Tarnopolsky and colleagues examined gene expression associated with massage and then performed targeted reverse transcriptase-polymerase chain reaction studies, analyzed protein signaling, and quantified metabolite production.

As compared with baseline values, muscle tissue from the control leg exhibited changes in expression of 592 genes 30 minutes after exercise and 1,309 genes after the recovery period. Investigators identified five genes that exhibited changes in expression immediately after massage and four genes that differed in expression levels after the recovery period.

The five genes with altered expression immediately after massage included one that was functionally related to actin dynamics. One of the four genes with altered expression after the recovery period was related to nuclear factor kappa-B nuclear trafficking.

"Overall, this profile suggested that massage altered processes related to the cytoskeleton and to inflammation, with the former process being activated early after massage and the latter induced later in recovery," the authors wrote.

To examine muscle damage and activation of mechanical signaling, the investigators assessed focal adhesion kinase (FAK) and extracellular signal-regulated kinase 1/2 (ERK1/2), signaling proteins involved in mechanotransduction in skeletal muscle. Levels of both proteins were elevated immediately after massage, suggesting a role in the transmission of the mechanical stimulus of massage therapy.

Massage had no effect on key regulators of growth signaling and metabolite accumulation, including lactate, glycogen, proglycogen, and macroglycogen.

The investigators also found that massage was associated with increased expression of nuclear peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1-alpha), a mediator of tissue repair and metabolic control, after the recovery period. The observation was in accordance with increased expression of FAK, which controls expression of PGC-1-alpha.

Also after the post-massage recovery period, the authors found increased expression of COX7B and ND1 mRNA -- which are encoded by nuclear and mitochondrial genes and transcriptionally activated by PGC-1-alpha -- "confirming that mitochondrial biogenesis signaling was augmented by massage therapy."

In the immediate post-massage period, pro-inflammatory NF-kappa-B signaling was diminished. After the post-massage recovery period, phosphorylation of heat-shock protein 27 (a marker of cellular stress) was reduced compared with the control situation, as were concentrations of interleukin-6 and tumor necrosis factor-alpha.

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