We previously reported that serum IL-6 levels are adversely associated with lower extremity function in the year following hip fracture.9
In the current analyses, we explored whether muscle mass, strength or both explained this association. We found that although the overall interpretation of the longitudinal association between IL-6 group and LEGS changed little with the different models, adjustment for muscle mass attenuated the 12-month effect estimate by 5%, from 4.51 to 4.28 points whereas adjustment for muscle strength resulted in a 16% attenuation of the 12-month estimated effect form 4.51 to 3.81 points. Adjustment for both muscle mass and strength did not alter the effect estimate substantially over adjustment for strength alone. These results would suggest that the association of IL-6 with lower extremity function following hip fracture is explained by muscle strength in disproportion to muscle mass.
In studies of older adults, including adults post hip fracture, muscle strength, in disproportion to muscle mass, has been associated with poor function.12–14, 31
Our results are consistent with previous studies that have found that, in older adults, levels of inflammatory markers are more strongly associated with muscle strength than muscle mass32
and that changes in muscle strength may explain the association between IL-6 with functional loss.33
To our knowledge, however, this is the first study to examine these associations longitudinally in a cohort of frail older adults recovering from a traumatic and disabling event, hip fracture.
In a less disabled cohort of older adults, inflammatory cytokine levels have been found to be associated with low levels of muscle mass32
and, in turn, low muscle mass was associated with poor lower extremity function.34
In contrast, in this and other cohorts of elders post hip fracture, an association between aLM and lower extremity function was not found.12, 14
Although aLM is considered a measure of sarcopenia, its utility may be limited in the study of frail elders such as those recovering from hip fracture, where many may have low muscle mass. For example, in the cohort studied here, the mean (SD) aLM at the baseline examination was 13.9 (3.0) kg compared to published values of 16.1 (2.5) kg in older white women from the Health Aging and Body Composition (Health ABC) Study.32
Previously published analyses from the BHS-3 cohort have demonstrated that lean body mass decreases rapidly post hip fracture with, compared to the immediately post-fracture measurement, a decline of 6.4% noted by 2 months post fracture and a persistent decrease of 6.0% noted at one year. In contrast, fat mass was found to decrease by only 1.6% by 2 months and increase by 3.6% by 12 months post fracture, suggesting that the loss of lean tissue exceeds that of overall body mass.10
Low muscle mass is believed to be central to the frailty syndrome35
and therefore in frail elders, such as those who suffer hip fracture, changes in muscle mass may be small. Processes intrinsic to the muscle itself, however, such as alterations of contractile protein structure with resulting changes in muscle contractile properties may explain the observed declines in strength that are associated with inflammation.
Although the specific mechanisms that explain declines in muscle strength in older adults are not completely understood, factors such as age-associated decreases in the proportion of myosin heavy chain type II fibers,36
increased connective tissue, fatty infiltration, 37
altered muscle metabolism,38
and changes to the muscle spindle39
are believed to play a role. Single muscle fibers taken from older subjects have been found to have significantly lower maximal force compared with similar fibers from younger individuals, suggesting that the intrinsic ability of muscle fibers to generate force is lower in older subjects.40
Although single muscle fibers from old subjects are frequently smaller in cross sectional area (CSA) than those taken from younger individuals,37
the decline in force observed with aging exceeds this decrease in CSA.41
This may be explained, in part, by myosin concentration levels in muscle fibers from older and younger individuals as myosin concentration has been found to have a linear relationship with specific force (force/CSA) generation in single muscle fibers and these concentrations are lower in fibers taken from the skeletal muscle of older, compared to younger subjects.41
Inflammation can also affect muscle contractile properties. In addition to the catabolic effect of chronic inflammatory states,42, 43
tumor necrosis factor alpha (TNF-α) is believed to depress contractile force at the myofilament level, by a mechanism mediated by reactive oxygen species (ROS) and nitric oxide (NO) derivative generation.44
These results must be viewed with the following limitations in mind. As we have previously reported, a proportion of study subjects had cytokine levels beyond the range of the assays employed and, due to selective forces, serum samples at later evaluations were obtained from younger women with less comorbidity, compared to the cohort as a whole at baseline.9
Also, all of the subjects included in these analyses were white women and thus we are unable to assess whether similar associations exist in men or in women of other ethnicities. Finally, the association of IL-6 with both muscle strength and muscle mass observed here explained 19% of the relationship between this inflammatory cytokine and recovery of lower extremity function post hip fracture. This would suggest that these associations, although interesting, represent but one piece of a more complex mechanism and other processes, beyond the scope of study of these analyses, are also likely to be involved.
In summary, we have found that muscle strength in disproportion to muscle mass explains the association of serum levels of the inflammatory cytokine IL-6 with lower extremity function in the year after hip fracture. These results should be confirmed in studies where direct measures of muscle composition are available.