Lower muscle mitochondrial energetics is associated with greater phenotypic frailty in older women and men: the Study of Muscle, Mobility and Aging

Abstract

Background: Phenotypic frailty syndrome identifies older adults at greater risk for adverse health outcomes. Despite the critical role of mitochondria in maintaining cellular function, including energy production, the associations between muscle mitochondrial energetics and frailty have not been widely explored in a large, well-phenotyped, older population.

Methods: The Study of Muscle, Mobility and Aging (SOMMA) assessed muscle energetics in older adults (N = 879, mean age = 76.3 years, 59.2% women). ³¹Phosporous magnetic resonance spectroscopy measured maximal production of adenosine triphosphate (ATP_max) in vivo, while ex vivo high-resolution respirometry of permeabilized muscle fibers from the vastus lateralis measured maximal oxygen consumption supported by fatty acids and complex I- and II-linked carbohydrates (e.g., Max OXPHOS_CI+CII). Five frailty criteria, shrinking, weakness, exhaustion, slowness, and low activity, were used to classify participants as robust (0, N = 397), intermediate (1-2, N = 410), or frail (≥ 3, N = 66). We estimated the proportional odds ratio (POR) for greater frailty, adjusted for multiple potential confounders.

Results: One-SD decrements of most respirometry measures (e.g., Max OXPHOS_CI+CII, adjusted POR = 1.5, 95%CI [1.2,1.8], p = 0.0001) were significantly associated with greater frailty classification. The associations of ATP_max with frailty were weaker than those between Max OXPHOS_CI+CII and frailty. Muscle energetics was most strongly associated with slowness and low physical activity components.

Conclusions: Our data suggest that deficits in muscle mitochondrial energetics may be a biological driver of frailty in older adults. On the other hand, we did observe differential relationships between measures of muscle mitochondrial energetics and the individual components of frailty.

Keywords: Aging; Mitochondria; Muscle energetics; Phenotypic frailty.

Fig. 1

SOMMA participants with data for frailty and muscle mitochondrial energetics. Participants with missing data for these measures were due to *safety reasons preventing sampling and testing, or the data could not be calculated. CESD-10, 10-Item Center for Epidemiological Studies Depression Scale; CHAMPS, Community Health Activities Model Program for Seniors; D₃Cr, D₃-creatine dilution method; ³¹P MRS, phosphorous magnetic resonance spectroscopy; respirometry, high-resolution respirometry; SOMMA, Study of Muscle, Mobility and Aging

Fig. 2

Lower muscle mitochondrial energetics is associated with greater frailty in SOMMA older adults. Multivariate-adjusted means (age, sex, race, education, marital status, adiposity, height, smoking, alcohol, multimorbidity) of muscle mitochondrial measures in SOMMA older adults (age ≥ 70 years) by frailty status are shown with 95% confidence intervals (CI). A Oxidative phosphorylation (OXPHOS) measured with protocol 1 (carbohydrates) in permeabilized myofibers by high-resolution respirometry, N ≥ 569 for all measures. B OXPHOS measured with protocol 2 (carbohydrates and fatty acid (FAO)), N ≥ 504 for all measures. C P³¹ MRS measure of maximal adenosine triphosphate production (ATP_max), N ≥ 534. Significance levels for the comparison of the referent group (robust) to the intermediate and frail groups are denoted as *p < 0.05; **p < 0.01; ***p < 0.001. The p-trend across the three groups were denoted with †p < 0.05; ††p < 0.01; †††p < 0.001. Details of adjusted means and variable names are available in Supplementary Tables 2 and 3

Fig. 3

Older adults with lower muscle mitochondrial energetics have higher odds of greater frailty. Measures of association are proportional odds ratios (POR). Model 1 associations were adjusted for technician or site. Model 2 associations were adjusted for model 1 plus age, sex, race, education, marital status, adiposity, height, smoking, alcohol, and number of conditions. Panel shows POR of greater frailty by 1 SD decrement of A respirometry protocol 1 measures, N ≥ 569, B respirometry protocol 2 measures, N ≥ 504, and C ATP_max by ³¹P MRS, N ≥ 534. Use Supplementary Table 2 for variable name reference

Fig. 4

Muscle mitochondrial energetics is differentially associated with phenotypic frailty components. Comparisons were between older adults with an absence versus presence of each frailty component. The bar chart shows fully adjusted means of each group with 95% confidence intervals (CI) from model 2 (site or technician, age, sex, race, education, marital status, adiposity, height, smoking, alcohol, and number of multimorbidities with corresponding p-values: † < 0.05, † † < 0.01, and † † † < 0.001. p values from model 1 (site or technician) were also included: *< 0.05, **< 0.01, ***< 0.001, and ****< 0.0001. A Protocol 1 respirometry supported by complex I- and II-linked carbohydrates, B protocol 2 respirometry supported by complex I- and II–linked carbohydrates and fatty-acids, and C ³¹P MRS measure of ATP_max. The N reported is an approximation, as different participants could be missing various respirometry or ³¹P MRS measures