Strength Training (Progressive Resistive Exercise)

Strength training (progressive resistive exercise) increases lean body mass, muscle protein mass, contractile force, and power, and improves physical function. Lifting of weights during concentric (muscle shortens during contraction) or eccentric (muscle lengthens during contraction) exercise produces microinjuries to the sarcolemma and initiates transcriptional and splice mechanisms, protein turnover, and signaling pathways from hormone and cytokine receptors. This process involves several proteins that shuttle between sarcomeric and nonsarcomeric localizations and convey signals to the nucleus. Satellite cells, mononuclear cells, and myogenic progenitor cells that typically exist in a state of quiescence under the basal lamina are activated and fuse to the existing fiber, leading to proliferation of nuclei in the muscle, which provides the machinery for additional contractile proteins. Resistance exercise increases the DNA content in the myofibrils, which in turn increases the number of muscle proteins, especially actin and myosin.

Aerobic Exercise

Aerobic endurance training induces physiologic adaptations that differ from strength training. Aerobic training that involves the use of large muscle groups reciprocally for sufficient intensity and duration (30 minutes at 50%–85% of oxidative capacity [V o _2max ]) induces adaptations in the heart, peripheral circulation, and skeletal muscle systems. Greater oxygen delivery is achieved by training-induced increases in cardiac output (due to increased stroke volume), capillary density, and vascular conduction. Improved use of oxygen by trained skeletal muscle is accomplished by mitochondrial biogenesis and increased mitochondrial oxidative enzyme activity, which lead to an increased capacity to generate energy through oxidative phosphorylation in trained muscles. In healthy individuals, these adaptations play a major role in improving V o _2max and endurance, and reducing fatigue, as shown by the ability to perform submaximal work with less effort for longer duration. Endurance-trained individuals produce a lower concentration of blood lactate and lower heart rates than untrained individuals at the same level of submaximal exercise. Cessation of endurance training and resistance training leads to a reversal of benefits and to partial or marked reductions in the training-induced cardiopulmonary, vascular, and skeletal muscle benefits (deconditioning).

Dystrophinopathies

Several theories have been proposed to explain the pathogenesis of muscles from individuals with dystrophinopathies. Dystrophin deficiency destabilizes the dystrophin-glycoprotein complex, impairing localization of the dystroglycan and sarcoglycans to the muscle membrane, and compromising the structural integrity of the sarcolemma membrane. Dystrophin is a high molecular weight cytoskeleton protein localized at the inner surface of the muscle membrane, and is part of a dystrophin-glycoprotein complex that also includes dystroglycan and sarcoglycans. This dystrophin-glycoprotein complex provides a bridge across the muscle membrane; dystrophin couples F-actin in the cytoplasm with dystroglycan, which binds to merosin (laminin-2) in the extracellular matrix. Excessive mechanical stress creates micro- and macroinjuries to the sarcolemma membrane which, in turn, causes excessive calcium ion influx, phospholipase activation, oxidative muscle injury, and, ultimately, necrosis of the muscle fiber. As muscle damage progresses, connective tissue and fat replace the damaged muscle fibers. Disruption of the dystrophin complex downregulates neuronal nitric oxide synthase (nNOS), which disrupts the exercise-induced cell-signaling pathway that regulates blood flow to the muscle and results in functional muscle ischemia. Recent studies have shown that when nNOS is not present at its normal location on the muscle membrane, the blood vessels that supply active muscles do not relax normally and show signs of fatigue. Thus, the pathophysiology of the disease may significantly affect its response to exercise. Exercise, especially exercise that places a large amount of stress on the muscle fibers, such as high-resistive and eccentric exercise, damages skeletal muscle in the dystrophinopathies. Even mild exercise has been implicated in causing functional muscle ischemia and fatigue in dystrophinopathy patients, resulting from disruptions in nNOS signaling.

Limb-Girdle Muscular Dystrophies

Before the advent of genetic testing, patients commonly sharing a slowly progressive pattern of proximal greater than distal muscular weakness and classified as being of either autosomal recessive (type 2) or autosomal dominant (type 1) inheritance were termed as having LGMDs. Recent advances in molecular and genetic analyses have now identified several distinct genetic abnormalities with mutations in these patients. At present at least 22 subtypes of LGMD are recognized, and the list continues to grow. Eight have autosomal dominant inheritance (LGMD type 1, A–H) and 14 have autosomal recessive inheritance (LGMD type 2, A–N). It is now known that LGMD comprises many distinct diseases with genetic defects in genes that encode for sarcolemmal, sarcomeric, and sarcoplasmic proteins. The most common LGMDs include LGMD2A (calpainopathy), LGMD2B (dysferlinopathy), LGMD2C (γ-sarcoglycanopathy), LGMD2D (α-sarcoglycanopathy), LGMD2E (β-sarcoglycanopathy), LGMD2F (δ-sarcoglycanopathy), and LGMD2I.

The defects or loss of proteins encoded by these genes leads to a loss of sarcolemmal integrity and a progressive pattern of proximal greater than distal muscular weakness that is similar to that of the dystrophinopathies. Defects in these proteins render muscle fibers more susceptible to exercise-induced damage and the development of myoglobinuria. The reduction of nNOS levels in the sarcolemma of LGMD subjects alters their cell-signaling response to exercise and makes them more susceptible to injury and fatigue, in both humans and the dystrophin-deficient (mdx) and α-sarcoglycan deficient (Sgca) mouse.

The effect of exercise in LGMD subjects is mixed. Sveen and colleagues examined the effect of aerobic cycling in adults with mild LGMD2I, which is caused by a defect in fukutin-related protein, a sarcoplasmic enzyme that glycosylates dystroglycan needed for appropriate binding of the dystrophin-glycoprotein complex to laminin-2. The LGMD2I patients reported a 21% increase in V o _2max and a 27% increase in work capacity, as well as a self-reported increase in strength and endurance without any evidence of muscle damage, as observed by serum creatine kinase and muscle biopsy. Yeldan and colleagues reported that progressive resistance exercise improved respiratory function in 17 individuals with genetically confirmed LGMD and 6 with Becker muscular dystrophy. However, muscle response of respiratory muscles was specific to the training protocol. Deep-breathing exercises improved maximal expiratory pressure while inspiratory muscle training improved maximal inspiratory pressure; however, neither regimen significantly altered spirometry results. Böhme and Arnold examined the effect of intensive physical therapy in 156 patients with an LGMD and noted an improvement in functional parameters. The rarity of individuals with specific LGMDs and the lack of adequate genetic confirmation confound the difficulties in performing studies to determine the effect of exercise in these patients. As is true for the dystrophinopathies, high-resistance exercise training should be avoided in LGMD patients, especially those who are very weak.

Facioscapulohumeral Dystrophy

FSHD was clinically categorized by its characteristic progressive muscular weakness in the facial and shoulder girdle musculature and onset of symptoms in adolescence or early adulthood. More recent studies have shown that FSHD is an autosomal dominant disorder resulting from a chromosomal abnormality identified at the 4q35 gene locus that causes reduced DNA fragment size at the telomere region and epigenetic changes in the chromatin structure regulated by DUX4. In contrast to the other muscular dystrophies, there are few distinctive findings on muscle biopsy, with histology frequently demonstrating mild findings of atrophied fibers along with hypertrophied fibers; they do not undergo necrosis and regeneration as do those in dystrophinopathies and sarcoglycanopathies.

A randomized clinical trial was performed to assess the effect of progressive resistance strength training (3 times a week for 52 weeks) with and without albuterol in 65 FSHD subjects. No muscle damage was observed as a result of the training. Whereas the isometric strength of the elbow flexors did not increase between the exercised and nonexercised group, the dynamic strength increased more in the exercised group. Lindeman and colleagues suggested that different responses were due to the specificity of the training effect on dynamic strength. These results reiterate the need to develop proper outcome measures that are responsive to a specific type of exercise regimen. Because the weight training performed by van der Kooi and colleagues used isokinetic exercise, it is not surprising that the training resulted in larger increases in isokinetic strength compared with isometric strength. Whereas the elbows responded to the exercise training, the ankle dorsiflexors showed no significant changes as a result of the weight training. The lack of response in the ankle dorsiflexors may be attributed to an ineffective training regimen. However, the investigators noted that the dorsiflexors may not have been able to move against gravity and therefore might have been too weak to respond to the training regimen. The amount of weight used for training the dorsiflexors may have been insufficient to cause a training effect. The conflicting responses observed by the various muscles examined by van der Kooi and colleagues demonstrate the difficulties researchers face in developing an exercise prescription for each of the NMDs. The training needs to be optimized according to the initial strength of the patient, type of exercise, frequency of exercise, intensity of exercise, and the desired change, which are likely to differ depending on the muscle group that is being trained, the strength of the muscle, and the desired outcome (whether it is a change in isometric strength, isokinetic strength, or fatigue). Olsen and colleagues reported that low-intensity aerobic cycling at a heart rate corresponding to a work intensity of 65% of V o _2max for 35 minutes, 5 times a week for 12 weeks significantly increased the maximal oxygen uptake and workload in 8 subjects with FSHD, with no signs of muscle damage. Perhaps the most important outcome is not strength or V o _2max , but whether the exercise changes function, improves quality of life, and alters future health outcomes.

Myotonic Muscular Dystrophy (DM1 and DM2)

There are 2 subtypes of myotonic muscular dystrophy, DM1 and DM2 (dystrophia myotonica types 1 and 2). DM1 is caused by abnormal expansion of the CTG trinucleotide repeats in the Dystrophia Myotonica Protein Kinase (DMPK) gene on chromosome 19q13.3, whereas DM2 is caused by an abnormal expansion of the CCTG repeats in the Zinc Finger protein 9 (ZNF9) gene on chromosome 3q21. The expansion of the gene is thought to trigger an RNA-mediated process that creates a toxic RNA that modulates other transcripts, including the chloride channel. As a result, DM1 and DM2 are multisystem disorders affecting skeletal muscle, smooth muscle, myocardium, brain, and ocular structures. This condition may manifest clinically with cataracts, cardiac conduction defects, endocrine abnormalities, swallowing dysfunction, and skeletal muscle weakness and myotonia. As opposed to the dystrophinopathies and sarcoglycanopathies, which are characterized as being necrotic muscle diseases with regeneration, myotonic muscular dystrophy necrosis is rare. In DM1 and DM2, atrophy leads to progressive reduction in muscle mass and weakness.

Moderate-resistance exercise and aerobic training have been shown to be safe in patients with myotonic muscular dystrophy, although the benefits of these exercise programs are mixed. Lindeman and colleagues found few significant effects of progressive resistance exercise in a group of clinically diagnosed ambulatory subjects with myotonic dystrophy. Aldehag and colleagues reported that progressive resistance exercise of the hand function 3 times per week for 12 weeks significantly increased motor function and self-rated occupational performance in 5 patients with DM1. Orngreen and colleagues reported that 12 weeks of moderate aerobic training increased V o _2max by 14% and workload by 11% in patients with DM1, without any muscle damage as observed by serum creatine kinase or muscle pathology. The DM1 subjects had a self-reported increase in strength, endurance, and walking.