Physical activity unveils the relationship between mitochondrial energetics, muscle quality, and physical function in older adults

Abstract

Background: The concept of mitochondrial dysfunction in ageing muscle is highly controversial. In addition, emerging evidence suggests that reduced muscle oxidative capacity and efficiency underlie the aetiology of mobility loss in older adults. Here, we hypothesized that studying well-phenotyped older cohorts across a wide range of physical activity would unveil a range of mitochondrial function in skeletal muscle and in turn allow us to more clearly examine the impact of age per se on mitochondrial energetics. This also enabled us to more clearly define the relationships between mitochondrial energetics and muscle lipid content with clinically relevant assessments of muscle and physical function.

Methods: Thirty-nine volunteers were recruited to the following study groups: young active (YA, n = 2 women/8 men, age = 31.2 ± 5.4 years), older active (OA, n = 2 women/8 men, age = 67.5 ± 2.7 years), and older sedentary (OS, n = 8 women/11 men, age = 70.7 ± 4.7 years). Participants completed a graded exercise test to determine fitness (VO₂ peak), a submaximal exercise test to determine exercise efficiency, and daily physical activity was recorded using a tri-axial armband accelerometer. Mitochondrial energetics were determined by (i) ³¹ P magnetic resonance spectroscopy and (ii) respirometry of fibre bundles from vastus lateralis biopsies. Quadriceps function was assessed by isokinetic dynamometry and physical function by the short physical performance battery and stair climb test.

Results: Daily physical activity energy expenditure was significantly lower in OS, compared with YA and OA groups. Despite fitness being higher in YA compared with OA and OS, mitochondrial respiration, maximum mitochondrial capacity, Maximal ATP production/Oxygen consumption (P/O) ratio, and exercise efficiency were similar in YA and OA groups and were significantly lower in OS. P/O ratio was correlated with exercise efficiency. Time to complete the stair climb and repeated chair stand tests were significantly greater for OS. Interestingly, maximum mitochondrial capacity was related to muscle contractile performance and physical function.

Conclusions: Older adults who maintain a high amount of physical activity have better mitochondrial capacity, similar to highly active younger adults, and this is related to their better muscle quality, exercise efficiency, and physical performance. This suggests that mitochondria could be an important therapeutic target for sedentary ageing associated conditions including sarcopenia, dynapenia, and loss of physical function.

Keywords: Ageing; Cardiovascular fitness; Mitochondria; Physical function; Skeletal muscle.

Figure 1

Mid‐thigh muscle and adipose tissue volume. Panel A , representative mid‐thigh MR images from young active (YA), old active (OA), and old sedentary (OS) participants. Skeletal muscle is coloured dark green. Subcutaneous adipose tissue (SAT) is coloured red. Intermuscular adipose tissue (IMAT) is coloured light green. Panel B, mid‐thigh muscle volume was higher in the YA group when compared with OS. Physical activity partially preserved mid‐thigh muscle volume in the OA group. Panel C, SAT volume was higher in the OS group when compared with YA and OA groups. Panel D, IMAT volume was higher in the OS group when compared with YA. Physical activity partially prevented IMAT accumulation in the OA group. The letters ^A and ^B denote significant differences between groups (P < 0.05, one‐way analysis of variance followed by post‐hoc Tukey test). Data presented are mean ± standard error of the mean.

Figure 2

Muscle contractile performance and physical function. Panel A, left leg 1‐repitition maximum (1‐RM) was lower in the old active (OA) and old sedentary (OS) groups, compared with young active (YA). Panel B, muscle quality (1‐RM/left leg lean mass) was similar between YA and OA groups and lower in the OS group. Physical function was assessed via 4‐m walk test (from short physical performance battery), repeated chair stand (from short physical performance battery), and stair climb test. Panel C, there was no difference between groups in time to complete 4‐m walk test. Panel D, time to complete the repeated chair stand test was higher in the OS group when compared with the YA and OA groups. Panel E, time to complete the stair climb test was higher in the OS group when compared with YA and OA groups and higher in the OA when compared with YA. The letters ^A, ^B, and ^C denote significant differences between groups (P < 0.05, one‐way analysis of variance followed by post‐hoc Tukey test). Data presented are mean ± standard error of the mean.

Figure 3

Skeletal muscle mitochondrial energetics and intramyocellular lipid. Panels A and B. Maximal mitochondrial phosphorylation capacity synthetic rate (ATP_max) and phosphocreatine (PCr) recovery time were determined by ³¹P magnetic resonance spectrocopy. Panel A, ATP_max was lower in old sedentary (OS) compared with both young active (YA) and old active (OA) groups. Panel B, PCr recovery time was significantly longer for OS compared with OA and YA groups. Panels C and D. Mitochondrial respiratory capacity measured in permeabilized myofibers by high‐resolution respirometry. Panel C, OS had lower LEAK respiration (L_I, 5 mM glutamate, and 2 mM malate), adenosine diphosphate (4 mM) stimulated maximal complex I (P_I) and complex I and II (P_I+II, 10 mM succinate) oxidative phosphorylation (OXPHOS) respiration, and maximal electron transfer system capacity (E_I+II, FCCP, 2 μM steps), when compared to YA and OA groups. Panel D, OS had lower fatty acid supported LEAK respiration (L_FAO, 2 mM malate, and 25uM Palmitoylcarnitine), adenosine diphosphate (4 mM) stimulated maximal OXPHOS respiration supported by FAO (P_FAO,), and complex I and II supported FAO (P_I+II+FAO, 2 mM malate, 5 mM glutamate, and 10 mM succinate), when compared with OA and YA groups. Panel E, mitochondrial H₂O₂ emission in permeabilized myofibers was not different between groups. Panel F, mitochondrial efficiency (ATP_max/P_I+II respiration; P/O ratio) was lower in the OS group when compared with YA and OA groups. Panels G, OXPHOS protein expression was lower in the OS group compared to YA and OA. Panels H and I, skeletal muscle intramyocellular lipid (IMCL) content. Panel H, soleus IMCL accumulation was higher in the OS when compared with YA. Physical activity partially prevented soleus IMCL accumulation in the OA group. Panel I, tibialis anterior IMCL content was similar between groups. The letters ^A and ^B denote significant differences between groups (P < 0.05, one‐way analysis of variance and Tukey's honest significance difference post‐hoc test). Data presented are mean ± standard error of the mean.

Figure 4

Submaximal exercise efficiency. The old sedentary (OS) group had lower gross (Panel A) and net (Panel B) exercise efficiency compared to the active groups. The letters ^A and ^B denote significant differences between groups (P < 0.05, one‐way analysis of variance and Tukey's honest significance difference post‐hoc test). Data presented are mean ± standard error of the mean.

Figure 5

Scatter plots depicting actual measured versus predicted normalized 1 repetition maximum (A) and time taken to complete stair climb test (B). Data are from multiple regression models in Table 4 and are from the old active and old sedentary groups only (total n = 29). For (A): age, sex, maximal adenosine triphosphate synthetic rate, and soleus IMCL significantly contributed to the model. For (B), maximal adenosine triphosphate synthetic rate, leg lean mass, and VO₂peak significantly contributed to the model. Best‐fit trend line and 95% confidence intervals are included.