Muscle inflammation susceptibility: a prognostic index of recovery potential after hip arthroplasty?

Abstract

While elective total hip arthroplasty (THA) for end-stage osteoarthritis (OA) improves pain, mobility function, and quality of life in most cases, a large proportion of patients suffer persistent muscle atrophy, pain, and mobility impairment. Extensive skeletal muscle damage is unavoidable in these surgical procedures, and it stands to reason that poor recovery and long-term mobility impairment among some individuals after THA is linked to failed muscle regeneration and regrowth following surgery and that local muscle inflammation susceptibility (MuIS) is a major contributing factor. Here we present results of two integrated studies. In study 1, we compared muscle inflammation and protein metabolism signaling in elective THA (n=15) vs. hip fracture/trauma (HFX; n=11) vs. nonsurgical controls (CON; n=19). In study 2, we compared two subgroups of THA patients dichotomized into MuIS⁺ (n=7) or MuIS⁻ (n=7) based on muscle expression of TNF-like weak inducer of apoptosis (TWEAK) receptor (Fn14). As expected, HFX demonstrated overt systemic and local muscle inflammation and hypermetabolism. By contrast, no systemic inflammation was detected in elective THA patients; however, local muscle inflammation in the perioperative limb was profound in MuIS⁺ and was accompanied by suppressed muscle protein synthesis compared with MuIS⁻. Muscle from the contralateral limb of MuIS⁺ was unaffected, providing evidence of a true inflammation susceptibility localized to the muscle surrounding the hip with end-stage OA. We suggest MuIS status assessed at the time of surgery may be a useful prognostic index for muscle recovery potential and could therefore provide the basis for a personalized approach to postsurgery rehabilitation.

Keywords: inflammation; muscle atrophy; muscle protein metabolism; muscle regeneration; total hip arthroplasty.

Fig. 1.

Indexes of systemic inflammation. Serum IL-6 (A) and TNF-α (B) concentrations in controls (CON) vs. patients undergoing elective total hip arthroplasty (THA) vs. trauma/hip fracture (HFX) victims. Values are means ± SE. *Different from CON, P < 0.05. †Different from THA, P < 0.05.

Fig. 2.

Inflammatory profile of muscle surrounding surgical hip. A: muscle gene expression in patients undergoing elective THA vs. HFX victims of 3 proinflammatory cytokines [IL-6, TNF-α, and TNF-like weak inducer of apoptosis receptor (TWEAK-R)] and their receptors relative to the CON group (dotted line). Values are means ± SD. *Different from CON, P < 0.05. †Different from THA, P < 0.05. B: muscle protein signaling results. S727 phosphorylation of STAT3 is plotted. A.U., arbitrary units. Values are means ± SE. *Different from CON, P < 0.05. †Different from THA, P < 0.05. C: representative immunoblots.

Fig. 3.

Muscle protein metabolism and putative regulators in muscle surrounding surgical hip. A: muscle protein fractional synthesis (FSR) and breakdown (FBR) rates in patients undergoing elective THA vs. HFX victims. †Different from THA, P < 0.05. B: muscle gene expression in THA vs. HFX of atrogin-1, IGF-I, and IGF-I receptor relative to the control (CON) group (dotted line). *Different from CON, P < 0.05. †Different from THA, P < 0.05. C: muscle protein signaling results. T32 phosphorylation of FOXO3a is plotted. All values are means ± SE. *Different from CON, P < 0.05. †Different from THA, P < 0.05. D: representative immunoblots.

Fig. 4.

Proinflammatory gene expression profile of contralateral muscle in patients undergoing elective THA vs. HFX victims relative to the CON group (dotted line). Values are means ± SD. *Different from CON, P < 0.05. †Different from THA, P < 0.05.

Fig. 5.

Inflammatory profile of muscle surrounding surgical hip in THA patients classified as muscle inflammation susceptibility positive vs. negative [MuIS⁽⁻⁾ vs. MuIS⁽⁺⁾]. A: THA patients dichotomized into MuIS⁽⁻⁾ vs. MuIS⁽⁺⁾ based on TWEAK-R gene expression. TWEAK-R expression was 5-fold higher in MuIS⁽⁺⁾ than both CON and MuIS⁽⁻⁾. B: muscle expression profile of proteolytic (MuRF1 and atrogin-1) and inflammatory (IL-6, IL-6R, TNF, TNF-R, and TWEAK) genes in MuIS⁽⁻⁾ and MuIS⁽⁺⁾ relative to the CON group (dotted line). Values are means ± SD. *Different from CON, P < 0.05. †Different from MuIS⁽⁻⁾, P < 0.05.

Fig. 6.

Inflammatory TWEAK signaling in muscle surrounding surgical hip compared with contralateral limb in MuIS⁽⁺⁾ vs. MuIS⁽⁻⁾ THA patients. A: protein levels of TWEAK-R, TRAF6, and the phosphorylation of NF-κB p65 (S536). All values are means ± SE. *Different from CON, P < 0.05. †Different from MuIS⁽⁻⁾, P < 0.05. B: representative immunoblots.

Fig. 7.

Muscle protein synthesis rates in muscle surrounding the surgical hip and in the contralateral limb of MuIS⁽⁺⁾ vs. MuIS⁽⁻⁾ THA patients. Values are means ± SE. *Different from MuIS⁽⁻⁾, P < 0.05.