Declining Skeletal Muscle Function in Diabetic Peripheral Neuropathy

Diabetes mellitus (DM) affects 26 million people in the United States alone, while approximately another 79 million have prediabetes. Approximately 30% to 50% of patients with DM develop diabetic peripheral neuropathy (DPN).^{,  ,}  DPN, or chronic distal symmetrical polyneuropathy, has been defined by the Toronto Diabetic Neuropathy Expert Group as “a symmetrical, length-dependent sensorimotor polyneuropathy attributable to metabolic and microvessel alterations as a result of chronic hyperglycemia exposure and cardiovascular risk covariates.” DPN develops as a consequence of long-standing hyperglycemia, associated with metabolic derangements such as increased polyol flux, accumulation of advanced glycation end products, oxidative stress, abnormal protein kinase C activity, and other abnormalities that affect mitochondrial bioenergetics.^,  Metabolic and microvascular (MV) impairments in DPN damage the endoneurial capillaries that supply the peripheral nerves and lead to sensory loss, pain, and muscle weakness (Figure 1).

Individuals with long-standing DM are at high risk for devastating foot complications such as plantar ulcers, Charcot arthropathy, and amputations. DPN plays a key role in the development of diabetic foot complications. Nearly 30% of patients with DPN will develop a foot ulcer within 2 years of diagnosis of severe DPN. Despite several therapeutic approaches for wound treatment, ~15% to 20% of all diabetic foot ulcers require amputation.^,  Plantar ulcers occur in ~15% of all individuals with DM, with a high financial cost associated with ulcer-related episodes. Ineffective management of diabetic foot complications contributes substantially to the high rate of amputations seen in this population. More than 60% of all nontraumatic lower limb amputations occur in people with DM. Patients with chronic wounds account for 10% of the entire diabetic Medicare population and are responsible for a 4-fold increase in annual per capita health care expenditures, compared with patients with DM without these complications. Besides the enormous financial impact, diabetic foot complications have a profound negative effect on patients’ mortality and quality of life.^{,  ,  ,  ,}  Approximately 70% of patients with DPN die at 10 years after the initial diagnosis of DPN, with 50% of these deaths being cardiovascular related.^, 

A significant consequence of DPN on the skeletal muscle is the accelerated loss of muscle mass, compared with DM alone. Deficits in lower limb muscles reduce functional capacity and contribute to altered gait, increased fall risk, and impaired balance in patients with DPN. This scenario is an important concern for patients with DPN because their falls are likely to be injurious and lead to bone fractures, poorly healing wounds, and chronic infections that may require amputation.^{,  ,}  The benefits of combining moderate-intensity aerobic exercise with resistance training to improve glycemic control and insulin sensitivity in individuals with DM are well documented. However, little is known about the benefits of exercise in individuals with DPN. Exercise in DPN has been predominantly discouraged in the past because it was considered as a hazard to further exacerbate DPN and risk of falling or injury. However, recent studies have shown that moderate-intensity exercise programs can improve the cardiorespiratory function of patients with DPN and can partially reverse some of their symptoms.^,  It has been hypothesized that exercise can partially reverse DPN progression because it promotes MV dilation, reduces oxidative stress, and increases the abundance of neurotrophic factors, all of which are compromised in DPN. Exercise can also improve lower limb muscle function by inhibiting key metabolic pathways that cause hypoxia. Furthermore, activation of nitric oxide production as a result of exercise is a key mechanism to improve endothelial function in DPN (Figure 1).

The present review describes the current knowledge of the effects of DPN in the skeletal muscle, as well as promising results from exercise interventions targeted at improving DPN muscle function and symptom reversal. We also highlight the mechanistic insights acquired by using noninvasive magnetic resonance imaging (MRI) techniques that can help assess the efficacy of future interventions for DPN.

Prolonged DPN is known to result in significant skeletal muscle deficits in this patient population, including neurogenic muscle atrophy, loss of muscle strength, power, and endurance.^{,  ,  ,}  These factors synergistically contribute to altered gait and impaired balance, which is particularly important for patients with DPN given that their falls often lead to bone fractures and chronic infections^{,  ,}  that may require an amputation.^,  Here we report on the current state of knowledge in terms of the effects of DPN in skeletal muscle impairment.

A significant consequence of DPN on skeletal muscle is the accelerated loss of motor axons.^{,  ,  ,}  The loss of motor units has been reported in the intrinsic foot muscles and the dorsiflexors of the leg,^{,  ,}  as well as intrinsic hand muscles. The loss can approach 50% compared with age-matched healthy control subjects.^{,  ,}  Patients with DPN have been shown to have greater motor unit losses compared with patients with DM with no neuropathy. The size of existing motor units indicated by the motor unit potential is increased^,  through the traditional pattern of reinnervation after denervation.

Electromyography studies have shown that DPN results in greater fiber density in the dorsiflexor muscles. This pattern of denervation is accelerated in DPN, compared with nonneuropathic DM. It is clear that complete reinnervation cannot offset the loss of motor neurons, as muscle mass is highly reduced with DPN. Furthermore, accelerated reinnervation is associated with greater loss in dorsiflexor muscle strength. The incomplete reinnervation in DPN may partially be attributed to declines in neurotrophic factors. The loss of motor units results in muscle weakness, atrophy, and intramuscular fatty infiltration.^,  Motor unit loss is directly correlated with loss of muscle mass and increased intermuscular fat.

Motor neuron axon excitability is decreased in DM, although the muscle fiber excitability seems to be preserved in DPN. It has been known for 50 years that DM is associated with slower nerve conduction velocity. Slower conduction velocities have been reported in the tibial nerve,^{,  ,}  peroneal nerve,^{,  ,}  and median nerve.^,  In some cases, peroneal nerve responses in DPN cannot be detected. Declines in femoral nerve conduction have also been reported in patients with DM with no overt signs of neuropathy. The slower conduction velocities may be linked to enhanced muscle fatigue with DPN. Slower femoral nerve conduction velocities are also associated with higher blood glucose levels. In addition, motor unit discharge frequencies are reduced in DPN. These findings collectively show that the intact motor neurons in DPN have reduced function.

Reduced muscle volume of the intrinsic foot muscles,^{,  ,  ,}  as well as the muscles in the leg,^,  occurs with DPN. Over a 12-year period, patients with DPN had a 57% decline in dorsiflexor muscle volume (4.5% per year), a 61% decline in plantar flexion volume (5% per year), and a 29% loss in foot muscle volume (3% per year). These declines were greater for DPN compared with DM without neuropathy. Furthermore, the annual decline of muscle volume was related to neuropathy impairment scores at follow-up. Muscle atrophy is length dependent, with more distal muscle areas showing greater losses. Skeletal muscle atrophy may be related to increased advanced glycation end products and receptors or reduced insulin signaling in skeletal muscle. Adipose tissue in the muscle is increased in DPN, in particular in the posterior leg.^{,  ,}  Increases in intermuscular adipose tissue are tied to reduced physical function and ability to complete daily activities.

Declines in muscle strength with DPN have been reported in several muscles, including the ankle extensors (dorsiflexors),^{,  ,  ,  ,  ,  ,  ,}  ankle plantar flexors,^{,  ,  ,}  knee extensors,^,  and knee flexors.^,  As expected, the more distal ankle muscles experience greater losses in strength compared with the muscles of the thigh. Ankle dorsiflexors^{,  ,  ,}  generally exhibit a 15% to 30% reduction compared with healthy control subjects. Declines in strength of the leg muscles are between 3% and 6% per year, depending on the severity of the neuropathy.^,  Strength losses across the lower limb are more severe in DPN compared with DM without neuropathy.^{,  ,}  Thigh muscle strength has shown reductions in patients with DPN^,  but not in those with DM without neuropathy. Importantly, muscle strength losses across the thigh and leg muscles are associated with neuropathy scores.^{,  ,  ,} 

Muscle performance is generally diminished in DPN. Muscle atrophy directly contributes to the declines in muscle force.^{,  ,  ,}  Muscle relaxation rates are prolonged, partially attributed to decreased calcium handling as the smooth endoplasmic reticulum ATPase (SERCA) protein content is reduced with DPN. The rate of force development is also reduced with DPN, as indicated by a longer time to reach peak force.^,  Specific force relative to muscle area in the dorsiflexors has also been reported in DPN,^,  suggesting declines in muscle quality. However, the voluntary activation of skeletal muscle or ability to fully recruit the muscle seems to be preserved in DPN.^,  Muscle performance declines in DPN include enhanced muscle fatigue of the dorsiflexors and the knee extensors, indicated by a shorter time to task failure. This reduced muscular endurance is greater in DPN compared with DM without neuropathy.

The diminished endurance time is also related to slower motor nerve conduction velocity. Few data are available on striated muscle fiber type changes in DPN. Surprisingly, muscle fiber size was reportedly not reduced in DPN; however, these patients had a high body mass index, which may have offset changes in fiber diameter. Nonetheless, the results are in agreement with a major role of neurogenic atrophy in decreased muscle strength. Patients with DM type 1 have an increased proportion of type II fibers, which could result in reduced muscular endurance. Other data from electromyography studies suggest that DPN is associated with decreases in fast motor units, as the postactivation potentiation is reduced in DPN and twitch relaxation time is prolonged. However, fiber type proportion is not related to neuropathy scores or any measure of glucose control or duration of DM. DPN is associated with reduced ankle joint motion for both plantar and dorsiflexion.^,  Decreased muscle strength of the ankle plantar and dorsiflexors is associated with shorter stride length and reduced walking speed. Reaction time of the knee and ankle joint muscles is also reduced with DPN. In addition, reduced dorsiflexion range of motion has been tied to declines in mobility and decreased neuropathy scores. Changes in ankle joint range of motions, strength, and reaction time are likely critical factors in balance impairments and fall risk associated with DPN.

Declines in muscle performance in DPN may also be influenced by blood flow and perfusion. Blood flow reductions occur with DPN and may contribute to reduced muscle endurance. Vascular impairments include increased carotid artery intima media thickness and decreased brachial artery flow–mediated dilation with DM. MV density and function^{,  ,}  are compromised in DPN. L-arginine, an important substrate used in nitric oxide–dependent vasodilation, is reduced in DM and importantly related to the development of peripheral neuropathy and microangiopathies. Increased advanced glycation end products occurring in DPN may diminish vascular endothelial function through decreasing nitric oxide bioavailability.

Skeletal muscle metabolism is also decreased in DPN. Resting levels of high-energy phosphates are reduced in the diabetic foot.^,  Muscle oxidative capacity is reduced by >50% in DPN compared with DM without neuropathy. The reduced mitochondrial function in DPN is related to increased inflammatory cytokines. A reduction in oxidative enzymes and mitochondria content has also been reported in striated muscle of DM (see Review). Declines in oxidative capacity are also reflected in slower rates of oxygen consumption during exercise in DM.

Taken together, patients with DPN have shown greater skeletal muscle deficits compared with patients with DM. These deficits reduce functional capacity and result in impaired balance, making these patients susceptible to injuries that can lead to amputation.

Hyperglycemia is an important factor in the development of DPN. However, the pathophysiologic processes through which hyperglycemia causes DPN are not fully understood. Furthermore, large clinical studies (ACCORD [Action to Control Cardiovascular Risk in Diabetes], ADVANCE [Action in Diabetes and Vascular Disease: PreterAx and Diamicron Controlled Evaluation], and VADT [Veterans Affairs Diabetes Trial]) have shown that good glucose control alone is insufficient to reduce the occurrence of foot complications, including DPN. There are no US Food and Drug Administration–approved treatment options that target the underlying pathogenesis of DPN.^, 

Several treatments that specifically target pathogenic DPN mechanisms have been tested both on animal models and humans. Most therapies under evaluation attempt to block key metabolic pathways linked to DPN progression and/or improve nerve blood flow by stimulating angiogenesis. These include agents such as α-lipoic acid (an antioxidant targeting hyperglycemia-induced oxidative stress) and actovegin (an agent believed to stimulate oxygen use and cellular energy metabolism). Some revascularization studies suggest that improving tissue blood flow may alleviate DPN. However, despite encouraging early results,^{,  ,  ,  ,  ,  ,}  there are no therapies to prevent or reverse its progress.^, 

A growing body of literature supports the benefits of combining moderate-intensity aerobic exercise with resistance training to improve glycemic control and insulin sensitivity in individuals with DM. Current practice guidelines endorsed by the American Diabetes Association and the American College of Sports Medicine recommend 150 minutes per week of combination (ie, aerobic and resistance) training. Key parameters related to exercise prescription include the following: (1) intensity (50%–80% the maximum rate of oxygen consumption as measured during incremental exercise); (2) frequency (3–4 times per week); and (3) duration (30–60 min per session). The total length of programs ranges from 10 to 26 weeks. Evidence from the DARE (Diabetes Aerobic and Resistance Exercise) and HART-D (Health Benefits of Aerobic and Resistance Training in Individuals With Type 2 Diabetes) clinical trials^,  showed that a combination of aerobic and resistance training improved glycosylated hemoglobin levels, which was not achieved by aerobic or resistance training alone. Prescription of resistance training includes a consideration of the following: (1) intensity (usually 2–3 sets of 12 repetitions each); (2) number of exercises (between 3 and 9 exercises that involve large muscle groups such as bench press, seated row, leg press, back extensions); and (3) frequency (2–3 sessions per week). The total length of programs ranges from 26 to 36 weeks, with weekly increments in 10 or 12 repetition maximum weight. Supervision has been linked to adherence, and adherence, in turn, has been linked to the extent of improvements in postintervention glucose tolerance.^, 

Preliminary studies have shown that moderate-intensity supervised exercise programs that include aerobic and resistance training are well tolerated by patients with DPN. The patients can significantly improve their cardiorespiratory function and can also improve DPN symptoms, including nerve function and cutaneous innervation.^{,  ,}  In addition, exercise may lead to an improved vascular endothelial function in DPN. It has been hypothesized that exercise can partially reverse DPN progression because it promotes MV dilation, reduces oxidative stress, and increases the abundance of neurotrophic factors, all of which are compromised in DPN. It has been suggested that moderate-intensity aerobic exercise has an anti-inflammatory effect in patients with DM. However, these effects have not been confirmed in patients with DPN. Exercise may be able to improve lower limb muscle function by inhibiting key metabolic pathways that cause hypoxia. Furthermore, activation of nitric oxide production as a result of exercise is a key mechanism to improve endothelial function in DPN.

Resistance training in DPN has the potential to increase muscle mass and muscle strength that are severely reduced with DPN. Recently, functional rates of force development were improved after resistance training in DPN. The effect of resistance exercise and increased muscle mass is essential to improve glycemic control because skeletal muscle is typically responsible for the majority of whole body glucose uptake. Therefore, substantial increases in skeletal muscle mass alone would be expected to lower blood glucose levels. Furthermore, aerobic exercise is associated with improvements in glucose uptake through increases in glucose transporters. Aerobic exercise combined with resistance has been shown to increase metabolic flexibility in type 2 DM, allowing the body to increase glucose metabolism. Aerobic exercise has clearly been shown to improve mitochondrial function across many diseases and conditions. Improving mitochondrial function not only stands to increase glucose uptake and clearance but also induces improvements in oxidative capacity. The improvements in oxidative capacity for DPN would increase muscular endurance and functional performance.

One of the obstacles for the development of effective treatments for DPN is the lack of sensitive and objective tests to detect small changes in symptoms and signs seen in interventions. Typically, a diagnosis of DPN is based on the patient’s description of pain. Abnormal findings from clinical examinations are used to determine a neuropathy score. Symptoms can be assessed by using composed scores (ie, Total Symptom Score, Toronto Clinical Neuropathy Score, Neuropathy Symptom Score). Other diagnostic scores focus on neuropathic impairments, such as the appearance of the feet, neuropathic ulceration, loss of Achilles tendon reflexes, and reduced vibration perception when tested using a tuning fork.

These often-used scores, which rely on patients’ subjective experience, are extremely variable with poor reproducibility and are considered unsuitable for the successful performance of clinical trials. Motor nerve conduction velocities have been used as surrogate end points in clinical trials. They are highly reproducible and correlate well with underlying structural abnormalities. Although smaller sensory fibers play a large role early in the development of DPN and thus play a greater role in early DPN compared with larger motor nerve fibers, motor nerve conduction velocity is reduced with the further progression of DPN.^{,  ,  ,  ,  ,}  Minimally invasive skin biopsies can assess intraepidermal fiber density, but the results have shown considerable variability, even among controls, and their invasive nature remains a burden for patients and researchers.^,  Corneal confocal microscopy has shown early promising results for noninvasive detection and stratification of the severity of DPN.^,  However, the sensitivity and specificity of the technique for feet at risk of ulceration are moderate.

Several MRI techniques have been used to assess different aspects of DPN, including skeletal muscle structure, function, and peripheral nerves (Table). These tools have the potential to bring new mechanistic insights into the effects of DPN as well as to objectively measure small changes in DPN pathology as a result of intervention.