Skeletal muscle apoptotic signaling predicts thigh muscle volume and gait speed in community-dwelling older persons: an exploratory study

Abstract

Background: Preclinical studies strongly suggest that accelerated apoptosis in skeletal myocytes may be involved in the pathogenesis of sarcopenia. However, evidence in humans is sparse. In the present study, we investigated whether apoptotic signaling in the skeletal muscle was associated with indices of muscle mass and function in older persons.

Methodology/principal findings: Community-dwelling older adults were categorized into high-functioning (HF) or low-functioning (LF) groups according to their short physical performance battery (SPPB) summary score. Participants underwent an isokinetic knee extensor strength test and 3-dimensional magnetic resonance imaging of the thigh. Vastus lateralis muscle samples were obtained by percutaneous needle biopsy and assayed for the expression of a set of apoptotic signaling proteins. Age, sex, number of comorbid conditions and medications as well as knee extensor strength were not different between groups. HF participants displayed greater thigh muscle volume compared with LF persons. Multivariate partial least squares (PLS) regressions showed significant correlations between caspase-dependent apoptotic signaling proteins and the muscular percentage of thigh volume (R(2) = 0.78; Q(2) = 0.61) as well as gait speed (R(2) = 0.81; Q(2) = 0.56). Significant variables in the PLS model of percent muscle volume were active caspase-8, cleaved caspase-3, cytosolic cytochrome c and mitochondrial Bak. The regression model of gait speed was mainly described by cleaved caspase-3 and mitochondrial Bax and Bak. PLS predictive apoptotic variables did not differ between functional groups. No correlation was determined between apoptotic signaling proteins and muscle strength or quality (strength per unit volume).

Conclusions/significance: Data from this exploratory study show for the first time that apoptotic signaling is correlated with indices of muscle mass and function in a cohort of community-dwelling older persons. Future larger-scale studies are needed to corroborate these preliminary findings and determine if down-regulation of apoptotic signaling in skeletal myocytes will provide improvements in the muscle mass and functional status of older persons.

Figure 1. Multivariate PLS regression of caspase-dependent apoptotic signaling proteins versus percent muscle volume.

(a) The regression yielded a 4-component model explaining 78.3% of the overall Y variance (Q² = 0.61). Black triangles correspond to low-functioning participants; grey squares represent high-functioning subjects. (b) Regression coefficients of apoptotic signaling proteins according to the Marten's uncertainty test. Significant variables are represented by grey bars. Error bars indicate uncertainty limits.

Figure 2. Multivariate PLS regression of caspase-dependent apoptotic signaling proteins versus gait speed.

(a) The regression yielded a 4-component model explaining 81.3% of the overall Y variance (Q² = 0.56). Black triangles correspond to low-functioning participants; grey squares represent high-functioning subjects. (b) Regression coefficients of apoptotic signaling proteins according to the Marten's uncertainty test. Significant variables are represented by grey bars. Error bars indicate uncertainty limits.

Figure 3. Protein expression levels of active caspase-8 and cytosolic cytochrome c according to the median of percent muscle volume.

The content of active caspase-8 (a) and cytosolic cytochrome c (b) was higher in participants with percent muscle volume below (median −) the median value of the study sample (48.6%) relative to those with percent muscle volume above the median (median +). AU: arbitrary units.