Quadriceps muscle power and optimal shortening velocity are inversely related to angiotensin converting enzyme activity in older men

Introduction

Age-related sarcopenia, connected with deteriorating in muscle mass and function, is one of the most important factors determining functional status^1–3. That is why methods used to prevent age-related loss of muscle mass and function are still being sought. Physical activity especially with proper nutritional intervention may be potentially an effective management for sarcopenia⁴, but it is difficult to convince seniors to follow these recommendations. There are various attempts to use pharmacological agents to prevent loss of muscle mass, but the effectiveness of many of them still needs to be confirmed⁵. Taking Angiotensin Converting Enzyme Inhibitors (ACEI) is also being considered. ACEI are traditionally used among others as anti-hypertensive medications and in cardiovascular diseases or diabetic nephropathy treatment⁶, but there are also some hypotheses that using ACEI may modify muscle aging. For example, Onder et al.⁷ in a three-year observational study in a group of older women with hypertension and without congestive heart failure have shown that ACEI treatment may slow age-related decline in muscle strength. The authors of the article explain this effect with several mechanisms, such as: direct influence on mechanical and metabolic changes in muscles (shift of the myosin heavy chains of skeletal muscle toward the fatigue-resistant forms; increasing insulin sensitivity, glycogen storage and glucose uptake in skeletal muscle; reduction of kinin breakdown and, consequently, improved circulation and better glucose and amino acid uptake), suppression of inflammatory activation connected with muscle catabobolism, beneficial effect on the nutritional status (inhibition of interleukin-6, which, among others, reduces appetite and, consequently, may cause malnutrition)⁷.

Taking ACEI as well as the ACE genotype with insertion (II) of allele in gene, is associated with lower serum ACE activity^8,9. There are suggestions that the ACE genotype type predisposes one to be successful in certain sports¹⁰. ACE is a basic component of renin-angiotensin system (RAS), which converts angiotensin I (ang I) in angiotensin II (ang II). Ang II may in turn influence muscle performance¹¹. Williams et al.¹² reported that circulating ACE activity was correlated with isometric and isokinetic strength of quadriceps muscle strength in untrained man.

Even more important than muscle strength factor affecting functional performance in elderly population are muscle power and muscle contraction velocity^1,2. These factors are also more influenced by aging than muscle strength¹³. In addition to our recent research¹⁴, there are no reports on the effect of ACEI taking and serum ACE activity on muscle power and muscle contraction velocity in older population. In that study we have found association between serum ACE activity with optimal shortening velocity of quadriceps muscles in older women, but not with muscle strength and power. Because various sex-related factors can modify age-related muscle changes¹⁵, earlier reported sex-related differences in ACE activity¹⁶, as well as possible differences in absorption of medications (absorption in women may be slower due to reduced gastric acid secretion and gastrointestinal motility)¹⁷ we conducted similar study in the group of older men.

The goal of our study was to assess if taking ACEI can modify muscle performance in older man as well as to assess the association of serum ACE activity with muscle strength, power, muscle contraction velocity and functional performance

Methods

Results

Baseline characteristics of the men taking and not taking ACEI as well as taking and not taking angiotensin system blocking medications (ASBMs) are shown in Table 1. Participants taking ACEI did not differ in terms of age, anthropometric indicators, education level, grip strength, muscle power, contraction velocity, and ADL results. Patients taking ACEI took more medications and were characterized by lower level of ACE in blood samples and lower IADL status. Men from both groups did not differ with regard to the prevalence of most diseases (ischemic heart disease, stroke, cancer, osteoporosis, COPD, heart failure, diabetes, myocardial infarction), but men talking ACEI more often suffered from hypertension (p=0.0003).

Whereas participants taking ASBMs were more than two years older than subjects not taking ASBMs, they took more medications, had greater BMI, and did not differ in terms of majority of muscles function parameters (Pmax, Ʋopt, right handgrip strength), except for the left handgrip strength.

We have found a positive relationship between age and ACE activity in men not taking ACEI and in all studied patients. We have also found a negative correlation between ACE activity and Pmax (Figure 1) as well as with Ʋopt (Figure 2) in group of patients not taking ACEI and in the whole group of men (Table 2). Similar relationships were observed in group of men not taking any ASBMs – both Pmax (borderline significance) and Ʋopt were negatively correlated with serum ACE activity (Table 2).

Figure 1. Correlation between ACE activity and Pmax in patients not taking ACEI.

Figure 2. Correlation between ACE activity and Ʋopt in patients not taking ACEI.

However, when ACE activity and age were entered into the multiple regression analyses, age was the only selected variable to determine both Pmax and Ʋopt.

Discussion

In this study we have shown that muscle power and muscle contraction velocity were negatively correlated with ACE activity in patients not taking ACEI and in patients not taking any ASBMs. However, taking ACEI was not consistently associated with handgrip strength, muscle power, muscle contraction velocity, and functional performance in older men of the same age and with comparable anthropometric parameters.

In 2002, Onder et al.⁷ published an article suggesting that treatment with ACEI may be associated with slower decline in muscle strength and function in older women with hypertension. During the three-year observation the reduction in the muscle strength of the knee extensors and in walking speed was significantly lower in women who continuously used ACEI than in those who used other or did not used any hypertensives. Buford et al. also reported greater exercise-derived improvements in physical function for older ACEI users²⁴. In EELO Project, taking medicines modulating the effect of angiotensin II (both ACEI and angiotensin receptors blockers) was connected with better functional capacity and muscle strength in people over 60 year of age²⁵. In the present study, despite the fact that patients receiving any ASBMs were more than two years older than those who did not take ASBMs, they did not differ in terms of muscle power and Ʋopt. This is consistent with our last study in older women¹⁴. Women taking ACEI were almost two years older, had lower health status than women not taking ACEI, but these two groups did not differ in terms of handgrip strength, Pmax, Ʋopt and functional performance. These results may suggest effect of RAS system on muscle performance.

However, there are some studies which do not confirm clearly the protective effect of ACEI on muscle and functional performance and on improvement of the response to exercises training. Sumukadas et al.²⁶ did not find effects of ACEI therapy on functional status as well as on improvement in handgrip and quadriceps muscle strength in older people undergoing 20-week progressive exercise training in comparison with placebo. In nine-month follow-ups taking ACEI was connected with decreasing of ACE activity but there was no association between the changes in ACE activity and changes in muscle strength or functional capacity in older community dwelling subjects²⁷. Similarly, in the TRAIN study, the authors did not observe significant modifications in physical performance and handgrip strength after six-months of fosinopril use in older persons with high cardiovascular risk profile²⁸. In 4.4 years, a follow-up study²⁹ taking any from cardiovascular drugs (ACEI, statins or thiazides) was not associated with differences in handgrip strength decline in healthy older people.

Therefore, the results regarding the relationship between ACEI and maintaining/improving muscle mass and strength in older age are still inconsistent. Many additional factors can potentially influence this relationship, like concomitant diseases, the type and dosage of the drugs, genetic predisposition, lifestyle, etc. The key point may be the observation time. The longest period of observations mentioned above was 4.4 years²⁹, but some of them were shorter - even six months²⁸. Decreasing muscle mass and function is not a rapid process. It has been reported that the strength loss in older men is 2–3.4% per year and is modulated by some other factors³⁰. Moreover, in one observation 15% of subjects older than 60 did not at all decline handgrip strength during the average nine-year follow-up³¹. Therefore, taking ACEI may be too weak a factor to notice its impact on maintaining muscle mass and function in a relatively short period of time and a longer follow-up is needed to confirm the importance of ACEI in this area.

This seems also likely in the context of our research. The main effect of ACEI use is the decrease of ACE activity⁸. Our results show that men with higher serum ACE activity are characterized by lower Pmax as well as lower Ʋopt. These correlations apply only to groups of patients not taking ACEI, not taking any ASBMs and all studied men, but not men taking ACEI or ASBMs. In men taking ACEI or other ASBMs in whom pharmacotherapy modulated ACE activity, this relationship is not clear. We also did not observe a similar relationship in relation to the handgrip strength. Interestingly, even if the relationships between ACE activity and muscle function (strength, power, contraction velocity) did not reach statistical significance, the direction of the association has always been the same - lower ACE activity was associated with better muscle function. This observation applies to all indicators of muscle function and to all analyzed patients’ subgroups in both our latest¹⁴ and current study. Statistically significant dependence in our last work in older women was demonstrated only for ACE activity and Ʋopt¹⁴. In the current study, in addition to Ʋopt also Pmax is negatively correlated with ACE activity, but handgrip strength is not. Ʋopt may be a more sensitive indicator of muscle function than strength and Pmax (force and velocity indicator), decreases with age faster than strength¹³. Our male group is older than previous group of women. Therefore, higher ACE activity had a chance to have a longer impact on the muscles. In both male groups (taking and not taking ACEI) higher ACE activity was also seen as compared to women.

This data seems also consistent with studies based on genetic tests. Serum ACE concentration is genetically determined (an insertion/deletion – I/D polymorphism in the ACE gene)⁹, so depending on the genetic predisposition, reduced or increased ACE activity has been acting on the studied men for their entire life. ACE genotype and activity may be not related to muscle function tests in young subjects³². In contrast, among older people deletion polymorphism of ACE gene (DD), connected with higher level of angiotensin II, was associated with low muscle mass³³. Similarly, advanced cancer patients with DD ACE gene polymorphism were characterized by higher serum ACE activity but lower hand grip strength compared with ACE insertion group^34,35.

There are several mechanisms that can explain the effects of ACE activity on Ʋopt and Pmax. ACE is responsible for the conversion of angiotensin I (ang-I) to angiotensin II (ang-II). Ang-II has vasoconstrictor effect, may decrease muscle blood flow and impair the delivery of insulin and glucose to skeletal muscle. The hyper-activity of RAS system may be therefore with an increased ACE activity, and thus with the hyper-activity of the RAS system. This hyper-activity may be associated with tissue insulin resistance³⁶. In addition it may also stimulate mitochondrial dysfunction, oxidative stress, and promote inflammatory processes³⁶ what may be connected with muscle atrophy. Ang-II also induces protein degradation through reactive oxygen species accumulation³⁶. Thus, lower ACE activity may limit muscle atrophy and the associated decline in muscle function (strength, power, contraction velocity). Lower ACE activity also have a neuroprotective effect^37,38 what is crucial because neural mechanisms are important factors in the development of sarcopenia³⁹.

Conditions such as heart failure, renal failure, chronic obstructive pulmonary disease, and cancer are associated with increased activation of the RAS pathway. These conditions can contribute to muscle atrophy, and thus also the decline in muscle function³⁶.

Since ACE activity in our study was positively correlated with age, we decided to conduct multiple regression analyses for determinants of both Pmax and Ʋopt including ACE activity and age as independent variables. In these analyses age was the only selected variable determining Pmax and Ʋopt. The positive relationship between ACE activity and age was surprising, but there were no studies in such advanced age so far. In a few works on this subject, serum ACE activity increased with age in children up to 18 years old⁴⁰ but did not vary with age in adults^41,42 or even decreased in rats⁴³ and in adult men⁴⁴.

Conclusions

Serum ACE activity negatively determines muscle power and muscle contraction velocity but not muscle strength in older men. The issues related to the impact of taking ACEI on the maintenance of muscle function and functional performance in older man require further studies with long-term follow-up, and determining the type and dose of the treatment.

Data availability