Background

There is increasing interest in the contribution of sarcopenia to frailty and ageing, but research in this area is hampered by the lack of accurate non-invasive measures of muscle function. Though a number of assessments related to muscle function are available, including tests of muscle strength, and functional assessments such as timed chair raise and 'get-up-and-go', objective imaging-based techniques are very limited. Measurement of lean mass, for example by DXA scanning, provides one potential option, based on evidence that this is related to muscle strength and physical activity. However, the overall amount of muscle provides limited information as to its function, suggesting the need for other imaging modalities. One such candidate is pQCT-based measurement of muscle density. However, rather than muscle function, it may be that this primarily provides a measure of intramuscular fat. Consistent with this suggestion, we recently reported a relatively strong inverse correlation between muscle density and total body fat mass (1). A similar relationship was reported between muscle density and insulin levels, consistent with the fact that intramuscular fat deposition is thought to represent an initial step in the development of insulin resistance.

Aims

In the present proposal, we aim to address the hypothesis that muscle density as measured by pQCT provides useful information about muscle function, which is independent of estimates of fat mass/insulin resistance. This will be investigated by examining whether muscle density (adjusted for fat mass) is related to relevant environmental factors such as physical activity, or to genetic factors unrelated to obesity (this research programme will also link in with a parallel project involving Celia Gregson using the Hertfordshire cohort, intended to examine relationships between equivalent pQCT-derived measured of muscle density and findings from muscle biopsies).

Methods

Outcome variables:

Muscle density and cross sectional area as measured by tibial pQCT at 15.5 and 17.5 clinic visits.

Exposures:

Moderate and/or vigorous physical activity, based on Actigraph measures at age 15.5 years, as previously used to examine relationships with other pQCT-derived variables at age 15.5 (2).

High impact activity, based on Newtest monitors at age 17.5 years, as previously used to examine relationships with other pQCT variables at age 17.5 (K Deere et al, JCEM, In Press).

Genome-wide genetic markers, imputed to the latest version of hapmap, as used in our recent GWAS studies of other pQCT parameters in our pQCT consortium (3) (discovery cohorts: ALSPAC, GOOD, Young Finns; replication cohorts: Mr Os, Hertfordshire, EMAS; second meta-analysis centre: University of Gothenberg).

Confounders: age, gender, height, weight, subcutaneous fat area (pQCT), lean mass, fat mass.

1. Sayers A, Lawlor DA, Sattar N, Tobias JH. The association between insulin levels and cortical bone: findings from a cross-sectional analysis of pQCT parameters in adolescents. J Bone Miner Res. 2012;27(3):610-8. Epub 2011/11/19.

2. Sayers A, Mattocks C, Deere K, Ness A, Riddoch C, Tobias JH. Habitual levels of vigorous, but not moderate or light, physical activity is positively related to cortical bone mass in adolescents J Clin Endocrinol Metab. 2011;In Press.

3. Paternoster L, Lorentzon M, Vandenput L, Karlsson MK, Ljunggren O, Kindmark A, et al. Genome-wide association meta-analysis of cortical bone mineral density unravels allelic heterogeneity at the RANKL locus and potential pleiotropic effects on bone. PLoS Genet. 2010;6(11):e1001217.